chr14-23360281-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. 16/24 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.

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

Publications

8 publications found

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 was made for transcript

Our verdict: Benign. The variant received -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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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

GnomAD2 exomes

AF:

0.0115

AC:

2796

AN:

242864

AF XY:

0.0115

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 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

African (AFR)

AF:

0.00207

AC:

AN:

33270

American (AMR)

AF:

0.00256

AC:

112

AN:

43730

Ashkenazi Jewish (ASJ)

AF:

0.00811

AC:

207

AN:

25526

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39642

South Asian (SAS)

AF:

0.00182

AC:

155

AN:

85338

European-Finnish (FIN)

AF:

0.0147

AC:

776

AN:

52958

Middle Eastern (MID)

AF:

0.00140

AC:

AN:

5720

European-Non Finnish (NFE)

AF:

0.0195

AC:

21571

AN:

1108996

Other (OTH)

AF:

0.0127

AC:

763

AN:

60040

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

1381

2762

4143

5524

6905

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

766

1532

2298

3064

3830

<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

AF:

0.0112

AC:

1700

AN:

152154

Hom.:

Cov.:

AF XY:

0.00991

AC XY:

737

AN XY:

74386

show subpopulations

African (AFR)

AF:

0.00323

AC:

134

AN:

41520

American (AMR)

AF:

0.00458

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00721

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5152

South Asian (SAS)

AF:

0.00207

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.0109

AC:

116

AN:

10598

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0194

AC:

1317

AN:

67994

Other (OTH)

AF:

0.00853

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

181

272

362

453

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0154

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

(source)

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;.;.

PhyloP100

1.7

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

Mutation Taster

=76/24

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over