Genetic Variant EFS:p.Ala560Ser (chr14-23357234-C-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_005864.4(EFS):c.1678G>T(p.Ala560Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

EFS
NM_005864.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.76

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:

ENSG00000259018 (HGNC:):

ENSG00000259018 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.33712918).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EFS	NM_005864.4 link	c.1678G>T	p.Ala560Ser	missense_variant	Exon 6 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.1678G>T	p.Ala560Ser	missense_variant	Exon 6 of 6	1	NM_005864.4	ENSP00000216733.3	O43281-1
EFS	ENST00000351354.3 link	c.1399G>T	p.Ala467Ser	missense_variant	Exon 5 of 5	1		ENSP00000340607.3	O43281-2
EFS	ENST00000429593.6 link	c.1171G>T	p.Ala391Ser	missense_variant	Exon 6 of 6	2		ENSP00000416684.2	O43281-3
ENSG00000259018	ENST00000554010.1 link	n.*231C>A		downstream_gene_variant		3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1391844

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

682046

African (AFR)

AF:

0.00

AC:

AN:

32162

American (AMR)

AF:

0.00

AC:

AN:

39826

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22262

East Asian (EAS)

AF:

0.00

AC:

AN:

38526

South Asian (SAS)

AF:

0.00

AC:

AN:

75836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51192

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5412

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1069376

Other (OTH)

AF:

0.00

AC:

AN:

57252

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 18, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1678G>T (p.A560S) alteration is located in exon 6 (coding exon 6) of the EFS gene. This alteration results from a G to T substitution at nucleotide position 1678, causing the alanine (A) at amino acid position 560 to be replaced by a serine (S). 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

Benign

0.097

BayesDel_addAF

Benign

-0.051

BayesDel_noAF

Benign

-0.31

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.19

T;.;.

Eigen

Uncertain

0.39

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.78

T;T;T

M_CAP

Benign

0.038

MetaRNN

Benign

0.34

T;T;T

MetaSVM

Uncertain

-0.22

MutationAssessor

Uncertain

2.5

M;.;.

PhyloP100

3.8

PrimateAI

Benign

0.40

PROVEAN

Benign

-2.1

N;N;N

REVEL

Benign

0.10

Sift

Uncertain

0.0030

D;D;D

Sift4G

Uncertain

0.030

D;T;T

Polyphen

0.63

P;.;D

Vest4

0.34

MutPred

0.26

Gain of disorder (P = 0.0448);.;.;

MVP

0.81

MPC

0.24

ClinPred

0.94

GERP RS

3.7

Varity_R

0.14

gMVP

0.30

Mutation Taster

=74/26

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