14-23358880-G-A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_005864.4(EFS):c.1247C>T(p.Pro416Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000621 in 1,610,524 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000064 ( 0 hom. )

Consequence

EFS
NM_005864.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.168

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 -4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.059987754).

BP6

Variant 14-23358880-G-A is Benign according to our data. Variant chr14-23358880-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 4016615.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EFS	NM_005864.4 link	c.1247C>T	p.Pro416Leu	missense_variant	Exon 5 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.1247C>T	p.Pro416Leu	missense_variant	Exon 5 of 6	1	NM_005864.4	ENSP00000216733.3	O43281-1
EFS	ENST00000351354.3 link	c.968C>T	p.Pro323Leu	missense_variant	Exon 4 of 5	1		ENSP00000340607.3	O43281-2
EFS	ENST00000429593.6 link	c.740C>T	p.Pro247Leu	missense_variant	Exon 5 of 6	2		ENSP00000416684.2	O43281-3

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152108

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000202

AC:

AN:

247840

AF XY:

0.0000298

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000357

Gnomad OTH exome

AF:

0.000166

GnomAD4 exome

AF:

0.0000638

AC:

AN:

1458416

Hom.:

Cov.:

AF XY:

0.0000634

AC XY:

AN XY:

725500

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33368

American (AMR)

AF:

0.00

AC:

AN:

44162

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25930

East Asian (EAS)

AF:

0.00

AC:

AN:

39650

South Asian (SAS)

AF:

0.0000467

AC:

AN:

85598

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53190

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.0000747

AC:

AN:

1110516

Other (OTH)

AF:

0.0000996

AC:

AN:

60246

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152108

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74288

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41416

American (AMR)

AF:

0.00

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000103

AC:

AN:

68026

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000989

Hom.:

Bravo

AF:

0.0000302

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000594

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

May 21, 2025

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.77

CADD

Benign

5.2

(source)

DANN

Benign

0.81

DEOGEN2

Benign

0.078

T;.;.

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.017

LIST_S2

Benign

0.61

T;T;T

M_CAP

Benign

0.0043

MetaRNN

Benign

0.060

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.55

N;.;.

PhyloP100

-0.17

PrimateAI

Benign

0.31

PROVEAN

Uncertain

-2.5

D;N;D

REVEL

Benign

0.031

Sift

Benign

0.072

T;T;T

Sift4G

Benign

0.24

T;D;D

Polyphen

0.56

P;.;B

Vest4

0.15

MVP

0.12

MPC

0.14

ClinPred

0.068

GERP RS

0.78

Varity_R

0.063

gMVP

0.40

Mutation Taster

=99/1

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.

14-23358880-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