NM_021922.3:c.229C>A

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_021922.3(FANCE):c.229C>A(p.Pro77Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000567 in 1,301,090 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00055 ( 0 hom. )

Consequence

FANCE
NM_021922.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:9O:1

Conservation

PhyloP100: 2.87

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 -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.008624077).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FANCE	NM_021922.3 link	c.229C>A	p.Pro77Thr	missense_variant	Exon 1 of 10	ENST00000229769.3	NP_068741.1	Q9HB96

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
FANCE	ENST00000229769.3 link	c.229C>A	p.Pro77Thr	missense_variant	Exon 1 of 10	1	NM_021922.3	ENSP00000229769.2	Q9HB96
FANCE	ENST00000696264.1 link	c.229C>A	p.Pro77Thr	missense_variant	Exon 1 of 8			ENSP00000512511.1	A0A8Q3WL50
FANCE	ENST00000648059.1 link	n.229C>A		non_coding_transcript_exon_variant	Exon 1 of 11			ENSP00000497902.1	A0A3B3ITU7
FANCE	ENST00000696265.1 link	n.229C>A		non_coding_transcript_exon_variant	Exon 1 of 9			ENSP00000512512.1	A0A8Q3WMB8

Frequencies

GnomAD3 genomes

AF:

0.000663

AC:

101

AN:

152230

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.0187

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00112

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000403

AC:

AN:

27270

Hom.:

AF XY:

0.000421

AC XY:

AN XY:

16616

show subpopulations

Gnomad AFR exome

AF:

0.00238

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00103

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000555

AC:

637

AN:

1148742

Hom.:

Cov.:

AF XY:

0.000553

AC XY:

307

AN XY:

555160

show subpopulations

Gnomad4 AFR exome

AF:

0.0000834

Gnomad4 AMR exome

AF:

0.000311

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000241

Gnomad4 FIN exome

AF:

0.0000786

Gnomad4 NFE exome

AF:

0.000646

Gnomad4 OTH exome

AF:

0.000282

GnomAD4 genome

AF:

0.000663

AC:

101

AN:

152348

Hom.:

Cov.:

AF XY:

0.000564

AC XY:

AN XY:

74500

show subpopulations

Gnomad4 AFR

AF:

0.000144

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.00112

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000279

Hom.:

Bravo

AF:

0.000601

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ExAC

AF:

0.000257

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:9Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Breakthrough Genomics, Breakthrough Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 03, 2021

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 22, 2019

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26580448, 25188385, 24728327, 27153395, 29146900) -

Fanconi anemia complementation group E

Uncertain:3

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Oct 28, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 77 of the FANCE protein (p.Pro77Thr). This variant is present in population databases (rs587778335, gnomAD 0.09%). This variant has not been reported in the literature in individuals affected with FANCE-related conditions. ClinVar contains an entry for this variant (Variation ID: 134330). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt FANCE protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Jun 05, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Uncertain:1Other:1

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

Feb 23, 2016

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

FANCE-related disorder

Uncertain:1

Feb 03, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The FANCE c.229C>A variant is predicted to result in the amino acid substitution p.Pro77Thr. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.10% of alleles in individuals of European (Non-Finnish) descent in gnomAD Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Fanconi anemia

Uncertain:1

Jul 20, 2021

Sema4, Sema4

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.47

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.32

Eigen

Uncertain

0.33

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.76

MetaRNN

Benign

0.0086

MetaSVM

Benign

-0.99

MutationAssessor

Uncertain

2.1

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-2.0

REVEL

Benign

0.21

Sift

Benign

0.23

Sift4G

Benign

0.10

Polyphen

0.96

Vest4

0.13

MVP

0.75

MPC

0.51

ClinPred

0.31

GERP RS

5.6

Varity_R

0.17

gMVP

0.23

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