rs552241929

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_021922.3(FANCE):c.52C>T(p.Pro18Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000205 in 1,321,212 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P18L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00021 ( 3 hom. )

Consequence

FANCE
NM_021922.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:2O:1

Conservation

PhyloP100: 0.915

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 Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.020660251).

BP6

Variant 6-35452597-C-T is Benign according to our data. Variant chr6-35452597-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 134331.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=3, not_provided=1}. Variant chr6-35452597-C-T is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FANCE	NM_021922.3 linkuse as main transcript	c.52C>T	p.Pro18Ser	missense_variant	1/10	ENST00000229769.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
FANCE	ENST00000229769.3 linkuse as main transcript	c.52C>T	p.Pro18Ser	missense_variant	1/10	1	NM_021922.3	P1
FANCE	ENST00000696264.1 linkuse as main transcript	c.52C>T	p.Pro18Ser	missense_variant	1/8
FANCE	ENST00000648059.1 linkuse as main transcript	c.52C>T	p.Pro18Ser	missense_variant, NMD_transcript_variant	1/11
FANCE	ENST00000696265.1 linkuse as main transcript	c.52C>T	p.Pro18Ser	missense_variant, NMD_transcript_variant	1/9

Frequencies

GnomAD3 genomes

AF:

0.000158

AC:

AN:

151802

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000580

Gnomad SAS

AF:

0.00186

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000579

AC:

AN:

50104

Hom.:

AF XY:

0.000831

AC XY:

AN XY:

30072

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00244

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000211

AC:

247

AN:

1169300

Hom.:

Cov.:

AF XY:

0.000266

AC XY:

151

AN XY:

566960

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000111

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000746

Gnomad4 SAS exome

AF:

0.00316

Gnomad4 FIN exome

AF:

0.0000795

Gnomad4 NFE exome

AF:

0.000106

Gnomad4 OTH exome

AF:

0.000191

GnomAD4 genome

AF:

0.000158

AC:

AN:

151912

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74276

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000582

Gnomad4 SAS

AF:

0.00187

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000270

Hom.:

Bravo

AF:

0.0000756

ExAC

AF:

0.000646

AC:

Asia WGS

AF:

0.000868

AC:

AN:

3472

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:2Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Fanconi anemia complementation group E

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Nov 03, 2021

- -

Fanconi anemia

Benign:1

Likely benign, criteria provided, single submitter

curation

Sema4, Sema4

Aug 24, 2021

- -

not specified

Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.29

Cadd

Benign

Dann

Uncertain

1.0

DEOGEN2

Benign

0.17

Eigen

Benign

0.0036

Eigen_PC

Benign

0.026

FATHMM_MKL

Benign

0.031

LIST_S2

Benign

0.59

M_CAP

Uncertain

0.21

MetaRNN

Benign

0.021

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.9

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-2.2

REVEL

Benign

0.064

Sift

Pathogenic

0.0

Sift4G

Benign

0.064

Polyphen

0.59

Vest4

0.15

MVP

0.73

MPC

0.53

ClinPred

0.27

GERP RS

4.0

Varity_R

0.33

gMVP

0.34

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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