6-35458438-C-T

Position:

chr6-35458438-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong

The NM_021922.3(FANCE):c.1111C>T(p.Arg371Trp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000613 in 1,613,900 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000064 ( 0 hom. )

Consequence

FANCE
NM_021922.3 missense, splice_region

Scores

Splicing: ADA: 0.9677

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 1.41

Variant links:

Genes affected

FANCE (HGNC:3586): (FA complementation group E) The Fanconi anemia complementation group (FANC) currently includes FANCA, FANCB, FANCC, FANCD1 (also called BRCA2), FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ (also called BRIP1), FANCL, FANCM and FANCN (also called PALB2). The previously defined group FANCH is the same as FANCA. Fanconi anemia is a genetically heterogeneous recessive disorder characterized by cytogenetic instability, hypersensitivity to DNA crosslinking agents, increased chromosomal breakage, and defective DNA repair. The members of the Fanconi anemia complementation group do not share sequence similarity; they are related by their assembly into a common nuclear protein complex. This gene encodes the protein for complementation group E. [provided by RefSeq, Jul 2008]

FANCE links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

PP5

Variant 6-35458438-C-T is Pathogenic according to our data. Variant chr6-35458438-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 566449.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-35458438-C-T is described in Lovd as [Likely_pathogenic]. Variant chr6-35458438-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FANCE	NM_021922.3 linkuse as main transcript	c.1111C>T	p.Arg371Trp	missense_variant, splice_region_variant	5/10	ENST00000229769.3	NP_068741.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FANCE	ENST00000229769.3 linkuse as main transcript	c.1111C>T	p.Arg371Trp	missense_variant, splice_region_variant	5/10	1	NM_021922.3	ENSP00000229769	P1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152066

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000119

AC:

AN:

251428

Hom.:

AF XY:

0.0000957

AC XY:

AN XY:

135906

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000289

Gnomad ASJ exome

AF:

0.000893

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000791

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000643

AC:

AN:

1461834

Hom.:

Cov.:

AF XY:

0.0000729

AC XY:

AN XY:

727232

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000380

Gnomad4 ASJ exome

AF:

0.00130

Gnomad4 EAS exome

AF:

0.000126

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000288

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152066

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74274

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000111

Hom.:

Bravo

AF:

0.0000604

ExAC

AF:

0.0000659

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Fanconi anemia complementation group E

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 11, 2024	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 371 of the FANCE protein (p.Arg371Trp). This variant is present in population databases (rs775076977, gnomAD 0.08%). This missense change has been observed in individuals with Fanconi anemia (PMID: 17924555, 22778927; Invitae). ClinVar contains an entry for this variant (Variation ID: 566449). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects FANCE function (PMID: 17308347). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	curation	Leiden Open Variation Database	Apr 08, 2012	Curator: Arleen D. Auerbach. Submitters to LOVD: Arleen D. Auerbach, Johan de Winter. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	May 26, 2023	The FANCE c.1111C>T (p.Arg371Trp) missense variant has been reported in a homozygous state in at least four individuals with Fanconi anemia (PMIDs: 17924555; 36463940; 22778927). This variant is reported in the Genome Aggregation Database in nine alleles at a frequency of 0.000868 in the Ashkenazi Jewish population (version 2.1.1). Data from the FANCE crystal structure suggest p.Arg371Trp may destabilize ternary protein conformation and experiments using a yeast two hybrid system indicate the variant disrupts the interaction between FANCE and FANC2 within the FA complex (PMID: 17308347). Based on the available evidence, the c.1111C>T (p.Arg371Trp) variant is classified as likely pathogenic for Fanconi anemia. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 09, 2024	- -

not provided

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 05, 2023	Reported in individuals with breast and/or ovarian cancer and an individual with head and neck squamous cell carcinoma (Maxwell et al., 2016; Chandrasekharappa et al., 2017; Jin et al., 2023); Published functional studies demonstrate a loss of interaction with FANCD2 in yeast (Nookala et al., 2007); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28678401, 33942288, 22778927, 19464302, 17924555, 17308347, 27153395, 36655350, 36845387, 32487094) -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 26, 2021	DNA sequence analysis of the FANCE gene demonstrated a sequence change, c.1111C>T, in exon 5 that results in an amino acid change, p.Arg371Trp. This sequence change has been described in gnomAD with a frequency of 0.087% in the Ashkenazi Jewish sub-population (dbSNP rs775076977). The p.Arg371Trp change affects a moderately conserved amino acid residue located in a domain of the FANCE protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Arg371Trp substitution. This sequence change has been reported in the homozygous state in several individuals with Fanconi anemia (PMID: 17924555, 22778927), as well as an individual affected with head and neck squamous cell carcinoma (PMID: 28678401). Functional studies have demonstrated that this missense change in disrupts FANCE√¢‚Ç¨‚ÄúFANCD2 interaction in yeast (PMID: 17308347). -

FANCE-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 05, 2024

The FANCE c.1111C>T variant is predicted to result in the amino acid substitution p.Arg371Trp. This variant, in the homozygous state or along with a second variant in FANCE, has been reported in several patients with Fanconi anemia (Ameziane et al. 2008. PubMed ID: 17924555; Gille et al. 2012. PubMed ID: 22778927, Nie et al. 2020. PubMed ID: 32487094; https://www2.rockefeller.edu/fanconi/genes/jumpe). This variant was also reported as likely pathogenic in a fetus with absence of radius or tibiofibular (Supplementary info 2 and Table S2, Zhang et al. 2021. PubMed ID: 33942288). Functional studies suggest that this variant is expected to alter protein structure and function (Nookala et al. 2007. PubMed ID: 17308347). This variant was also reported as a germline variant in one patient with head and neck carcinoma before age 50 (Table S3, Chandrasekharappa et al. 2017. PubMed ID: 28678401). This variant is reported in 0.087% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. This variant is interpreted as pathogenic. -

Fanconi anemia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 09, 2024

Variant summary: FANCE c.1111C>T (p.Arg371Trp) results in a non-conservative amino acid change located in the Fanconi Anaemia group E protein, C-terminal (IPR021025) of the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Three predict the variant weakens a 5' donor site. One predict the variant no significant impact on splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00012 in 251428 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in FANCE causing Fanconi Anemia (0.00012 vs 0.00048), allowing no conclusion about variant significance. c.1111C>T has been reported in the literature in individuals affected with Fanconi Anemia (Ameziane_2008, Gille_2012). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results loss of interaction with FANCD2 in yeast (Nookala_2007). The following publications have been ascertained in the context of this evaluation (PMID: 17924555, 17308347, 22778927). ClinVar contains an entry for this variant (Variation ID: 566449). Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

-0.082

BayesDel_noAF

Uncertain

-0.060

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.37

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Benign

0.64

LIST_S2

Uncertain

0.89

M_CAP

Benign

0.060

MetaRNN

Pathogenic

0.95

MetaSVM

Benign

-0.74

MutationAssessor

Uncertain

2.6

MutationTaster

Benign

1.0

PrimateAI

Benign

0.41

PROVEAN

Pathogenic

-5.3

REVEL

Uncertain

0.34

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.87

MutPred

0.85

Gain of catalytic residue at L369 (P = 0.0146);

MVP

0.79

MPC

0.54

ClinPred

0.67

GERP RS

3.5

Varity_R

0.64

gMVP

0.58

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.97

dbscSNV1_RF

Pathogenic

0.81

SpliceAI score (max)

0.11

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over