14-23359475-G-A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_005864.4(EFS):c.1003C>T(p.Arg335Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000163 in 1,591,788 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R335L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., cov: 30)

Exomes 𝑓: 0.00016 ( 1 hom. )

Consequence

EFS
NM_005864.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.193

Publications

0 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: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.14931554).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EFS	NM_005864.4 link	c.1003C>T	p.Arg335Trp	missense_variant	Exon 4 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.1003C>T	p.Arg335Trp	missense_variant	Exon 4 of 6	1	NM_005864.4	ENSP00000216733.3	O43281-1
EFS	ENST00000351354.3 link	c.724C>T	p.Arg242Trp	missense_variant	Exon 3 of 5	1		ENSP00000340607.3	O43281-2
EFS	ENST00000429593.6 link	c.496C>T	p.Arg166Trp	missense_variant	Exon 4 of 6	2		ENSP00000416684.2	O43281-3

Frequencies

GnomAD3 genomes

AF:

0.000152

AC:

AN:

151634

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00231

Gnomad EAS

AF:

0.000782

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000201

AC:

AN:

223634

AF XY:

0.000213

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00217

Gnomad EAS exome

AF:

0.000628

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000140

Gnomad OTH exome

AF:

0.000365

GnomAD4 exome

AF:

0.000165

AC:

237

AN:

1440038

Hom.:

Cov.:

AF XY:

0.000144

AC XY:

103

AN XY:

715180

show subpopulations

African (AFR)

AF:

0.000152

AC:

AN:

32870

American (AMR)

AF:

0.0000238

AC:

AN:

41972

Ashkenazi Jewish (ASJ)

AF:

0.00234

AC:

AN:

24792

East Asian (EAS)

AF:

0.000280

AC:

AN:

39250

South Asian (SAS)

AF:

0.0000239

AC:

AN:

83698

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49634

Middle Eastern (MID)

AF:

0.00288

AC:

AN:

5210

European-Non Finnish (NFE)

AF:

0.000103

AC:

114

AN:

1103180

Other (OTH)

AF:

0.000522

AC:

AN:

59432

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.522

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000152

AC:

AN:

151750

Hom.:

Cov.:

AF XY:

0.000135

AC XY:

AN XY:

74182

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41378

American (AMR)

AF:

0.00

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00231

AC:

AN:

3468

East Asian (EAS)

AF:

0.000784

AC:

AN:

5102

South Asian (SAS)

AF:

0.00

AC:

AN:

4792

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10598

Middle Eastern (MID)

AF:

0.00342

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000147

AC:

AN:

67828

Other (OTH)

AF:

0.00

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.516

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000433

Hom.:

Bravo

AF:

0.000162

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000260

AC:

ExAC

AF:

0.000185

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 13, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1003C>T (p.R335W) alteration is located in exon 4 (coding exon 4) of the EFS gene. This alteration results from a C to T substitution at nucleotide position 1003, causing the arginine (R) at amino acid position 335 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.66

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.20

CADD

Benign

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.56

D;.;.

Eigen

Uncertain

0.20

Eigen_PC

Benign

0.15

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.95

D;D;D

M_CAP

Uncertain

0.099

MetaRNN

Benign

0.15

T;T;T

MetaSVM

Benign

-0.45

MutationAssessor

Uncertain

2.3

M;.;.

PhyloP100

-0.19

PrimateAI

Pathogenic

0.83

PROVEAN

Uncertain

-4.0

D;D;D

REVEL

Benign

0.23

Sift

Pathogenic

0.0

D;D;D

Sift4G

Uncertain

0.0040

D;D;D

Polyphen

1.0

D;.;D

Vest4

0.63

MVP

0.83

MPC

0.54

ClinPred

0.26

GERP RS

1.2

Varity_R

0.29

gMVP

0.64

Mutation Taster

=86/14

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

14-23359475-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over