14-23360281-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_005864.4(EFS):c.298G>A(p.Val100Met) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0158 in 1,607,374 control chromosomes in the GnomAD database, including 249 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.011 ( 14 hom., cov: 32)

Exomes 𝑓: 0.016 ( 235 hom. )

Consequence

EFS
NM_005864.4 missense, splice_region

Scores

Splicing: ADA: 0.8433

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.73

Variant links:

Genes affected

EFS (HGNC:16898): (embryonal Fyn-associated substrate) The protein encoded by this gene is a member of the CAS (CRK-associated substrate) family of adaptor proteins which typically serve as scaffolds for the assembly of larger signaling complexes. These complexes form at the cell surface where integrin binding leads to the subsequent phosphorylation of a CAS protein. Additional binding of SRC family kinases leads to CAS hyperphosphorylation and the creation of binding sites for CRK and other proteins that cause actin cytoskeleton reorganization. This gene plays a role in integrin-mediated cell attachment, spreading, and migration and also plays a role in both normal and malignant cellular transformation. This broadly expressed gene has been shown to play a role in neurite outgrowth and its expression in the thymus and lymphocytes is important for T cell maturation and the development of immunological self-tolerance. Alternative splicing of this gene results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Jul 2020]

EFS links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.007813156).

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0112 (1700/152154) while in subpopulation NFE AF= 0.0194 (1317/67994). AF 95% confidence interval is 0.0185. There are 14 homozygotes in gnomad4. There are 737 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EFS	NM_005864.4 link	c.298G>A	p.Val100Met	missense_variant, splice_region_variant	Exon 3 of 6	ENST00000216733.8	NP_005855.1	O43281-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
EFS	ENST00000216733.8 link	c.298G>A	p.Val100Met	missense_variant, splice_region_variant	Exon 3 of 6	1	NM_005864.4	ENSP00000216733.3	O43281-1
EFS	ENST00000351354.3 link	c.19G>A	p.Val7Met	missense_variant, splice_region_variant	Exon 2 of 5	1		ENSP00000340607.3	O43281-2
EFS	ENST00000429593.6 link	c.19G>A	p.Val7Met	missense_variant, splice_region_variant	Exon 2 of 6	2		ENSP00000416684.2	O43281-3

Frequencies

GnomAD3 genomes

AF:

0.0112

AC:

1701

AN:

152036

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00324

Gnomad AMI

AF:

0.0110

Gnomad AMR

AF:

0.00459

Gnomad ASJ

AF:

0.00721

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00207

Gnomad FIN

AF:

0.0109

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0194

Gnomad OTH

AF:

0.00862

GnomAD3 exomes

AF:

0.0115

AC:

2796

AN:

242864

Hom.:

AF XY:

0.0115

AC XY:

1514

AN XY:

131232

show subpopulations

Gnomad AFR exome

AF:

0.00236

Gnomad AMR exome

AF:

0.00268

Gnomad ASJ exome

AF:

0.00822

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00172

Gnomad FIN exome

AF:

0.0136

Gnomad NFE exome

AF:

0.0201

Gnomad OTH exome

AF:

0.0107

GnomAD4 exome

AF:

0.0163

AC:

23662

AN:

1455220

Hom.:

235

Cov.:

AF XY:

0.0158

AC XY:

11430

AN XY:

723550

show subpopulations

Gnomad4 AFR exome

AF:

0.00207

Gnomad4 AMR exome

AF:

0.00256

Gnomad4 ASJ exome

AF:

0.00811

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00182

Gnomad4 FIN exome

AF:

0.0147

Gnomad4 NFE exome

AF:

0.0195

Gnomad4 OTH exome

AF:

0.0127

GnomAD4 genome

AF:

0.0112

AC:

1700

AN:

152154

Hom.:

Cov.:

AF XY:

0.00991

AC XY:

737

AN XY:

74386

show subpopulations

Gnomad4 AFR

AF:

0.00323

Gnomad4 AMR

AF:

0.00458

Gnomad4 ASJ

AF:

0.00721

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00207

Gnomad4 FIN

AF:

0.0109

Gnomad4 NFE

AF:

0.0194

Gnomad4 OTH

AF:

0.00853

Alfa

AF:

0.0167

Hom.:

Bravo

AF:

0.00994

TwinsUK

AF:

0.0170

AC:

ALSPAC

AF:

0.0195

AC:

ESP6500AA

AF:

0.00182

AC:

ESP6500EA

AF:

0.0199

AC:

171

ExAC

AF:

0.0120

AC:

1460

Asia WGS

AF:

0.00173

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.36

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.078

T;.;.

Eigen

Benign

0.11

Eigen_PC

Benign

0.13

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.80

T;T;T

M_CAP

Benign

0.025

MetaRNN

Benign

0.0071

T;T;T

MetaSVM

Benign

-0.57

MutationAssessor

Uncertain

2.3

M;.;.

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-1.6

N;N;N

REVEL

Benign

0.094

Sift

Uncertain

0.0040

D;D;D

Sift4G

Uncertain

0.018

D;D;D

Polyphen

0.66

P;.;P

Vest4

0.33

MPC

0.41

ClinPred

0.013

GERP RS

4.4

Varity_R

0.14

gMVP

0.48

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.84

dbscSNV1_RF

Benign

0.47

SpliceAI score (max)

0.010

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over