6-35452759-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_021922.3(FANCE):c.214C>T(p.Pro72Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. P72P) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 8.9e-7 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

FANCE
NM_021922.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 4.14

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 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FANCE	NM_021922.3 link	c.214C>T	p.Pro72Ser	missense_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.214C>T	p.Pro72Ser	missense_variant	Exon 1 of 10	1	NM_021922.3	ENSP00000229769.2
FANCE	ENST00000696264.1 link	c.214C>T	p.Pro72Ser	missense_variant	Exon 1 of 8			ENSP00000512511.1
FANCE	ENST00000648059.1 link	n.214C>T		non_coding_transcript_exon_variant	Exon 1 of 11			ENSP00000497902.1
FANCE	ENST00000696265.1 link	n.214C>T		non_coding_transcript_exon_variant	Exon 1 of 9			ENSP00000512512.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

8.88e-7

AC:

AN:

1126038

Hom.:

Cov.:

AF XY:

0.00000185

AC XY:

AN XY:

540954

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

23554

American (AMR)

AF:

0.00

AC:

AN:

10788

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

15940

East Asian (EAS)

AF:

0.00

AC:

AN:

26846

South Asian (SAS)

AF:

0.00

AC:

AN:

35522

European-Finnish (FIN)

AF:

0.00

AC:

AN:

24016

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3074

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

941090

Other (OTH)

AF:

0.0000221

AC:

AN:

45208

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Fanconi anemia complementation group E

Uncertain:2

Oct 17, 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 serine, which is neutral and polar, at codon 72 of the FANCE protein (p.Pro72Ser). 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: 408157). 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. -

Dec 14, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.55

BayesDel_addAF

Uncertain

0.044

BayesDel_noAF

Benign

-0.17

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.56

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.74

M_CAP

Benign

0.019

MetaRNN

Uncertain

0.67

MetaSVM

Benign

-0.68

MutationAssessor

Uncertain

2.1

PhyloP100

4.1

PrimateAI

Uncertain

0.69

PROVEAN

Uncertain

-2.7

REVEL

Benign

0.23

Sift

Benign

0.14

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.50

MutPred

0.57

Gain of phosphorylation at P72 (P = 0.0273);

MVP

0.81

MPC

0.53

ClinPred

0.97

GERP RS

5.2

PromoterAI

0.027

Neutral

(source)

Varity_R

0.17

gMVP

0.55

Mutation Taster

=89/11

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over