chr6-35452791-G-C

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_021922.3(FANCE):c.246G>C(p.Glu82Asp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000172 in 1,162,994 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Synonymous variant affecting the same amino acid position (i.e. E82E) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000017 ( 0 hom. )

Consequence

FANCE
NM_021922.3 missense, splice_region

Scores

Splicing: ADA: 0.00001106

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: -0.246

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

Fanconi anemia complementation group E
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P
Fanconi anemia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

FANCE links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.10908407).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FANCE	NM_021922.3 link	c.246G>C	p.Glu82Asp	missense_variant, splice_region_variant	Exon 1 of 10	ENST00000229769.3	NP_068741.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
FANCE	ENST00000229769.3 link	c.246G>C	p.Glu82Asp	missense_variant, splice_region_variant	Exon 1 of 10	1	NM_021922.3	ENSP00000229769.2
FANCE	ENST00000696264.1 link	c.246G>C	p.Glu82Asp	missense_variant, splice_region_variant	Exon 1 of 8			ENSP00000512511.1
FANCE	ENST00000648059.1 link	n.246G>C		splice_region_variant, non_coding_transcript_exon_variant	Exon 1 of 11			ENSP00000497902.1
FANCE	ENST00000696265.1 link	n.246G>C		splice_region_variant, non_coding_transcript_exon_variant	Exon 1 of 9			ENSP00000512512.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000172

AC:

AN:

1162994

Hom.:

Cov.:

AF XY:

0.00000177

AC XY:

AN XY:

563934

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

24412

American (AMR)

AF:

0.00

AC:

AN:

14678

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17740

East Asian (EAS)

AF:

0.00

AC:

AN:

27140

South Asian (SAS)

AF:

0.00

AC:

AN:

44846

European-Finnish (FIN)

AF:

0.00

AC:

AN:

26052

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3230

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

958182

Other (OTH)

AF:

0.0000428

AC:

AN:

46714

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Aug 26, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.246G>C (p.E82D) alteration is located in exon 1 (coding exon 1) of the FANCE gene. This alteration results from a G to C substitution at nucleotide position 246, causing the glutamic acid (E) at amino acid position 82 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

Fanconi anemia complementation group E

Uncertain:1

Sep 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 82 of the FANCE protein (p.Glu82Asp). This variant is not present in population databases (gnomAD no frequency). 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: 2556353). 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. 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.

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.35

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.55

CADD

Benign

(source)

DANN

Benign

0.83

DEOGEN2

Benign

0.22

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.69

M_CAP

Benign

0.021

MetaRNN

Benign

0.11

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.0

PhyloP100

-0.25

PrimateAI

Benign

0.45

PROVEAN

Benign

-0.81

REVEL

Benign

0.071

Sift

Benign

0.37

Sift4G

Uncertain

0.025

Vest4

0.10

ClinPred

0.079

GERP RS

0.54

PromoterAI

0.041

Neutral

(source)

Varity_R

0.094

gMVP

0.23

Mutation Taster

=86/14

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000011

dbscSNV1_RF

Benign

0.020

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over