dbSNP rs2231801: EFS:p.Val100Leu (chr14-23360281-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_005864.4(EFS):c.298G>T(p.Val100Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,455,232 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

EFS
NM_005864.4 missense, splice_region

Scores

Splicing: ADA: 0.7605

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.73

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.17285073).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EFS	NM_005864.4 link	c.298G>T	p.Val100Leu	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>T	p.Val100Leu	missense_variant, splice_region_variant	Exon 3 of 6	1	NM_005864.4	ENSP00000216733.3	O43281-1
EFS	ENST00000351354.3 link	c.19G>T	p.Val7Leu	missense_variant, splice_region_variant	Exon 2 of 5	1		ENSP00000340607.3	O43281-2
EFS	ENST00000429593.6 link	c.19G>T	p.Val7Leu	missense_variant, splice_region_variant	Exon 2 of 6	2		ENSP00000416684.2	O43281-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000206

AC:

AN:

1455232

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

723554

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33270

American (AMR)

AF:

0.00

AC:

AN:

43730

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25528

East Asian (EAS)

AF:

0.00

AC:

AN:

39642

South Asian (SAS)

AF:

0.00

AC:

AN:

85340

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52958

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5720

European-Non Finnish (NFE)

AF:

0.00000271

AC:

AN:

1109004

Other (OTH)

AF:

0.00

AC:

AN:

60040

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.408

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.36

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.50

CADD

Benign

(source)

DANN

Uncertain

0.97

DEOGEN2

Benign

0.061

T;.;.

Eigen

Benign

-0.37

Eigen_PC

Benign

-0.22

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.64

T;T;T

M_CAP

Benign

0.025

MetaRNN

Benign

0.16

T;T;T

MetaSVM

Benign

-0.89

MutationAssessor

Benign

1.6

L;.;.

PhyloP100

1.7

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-1.5

N;N;N

REVEL

Benign

0.052

Sift

Benign

0.26

T;D;D

Sift4G

Benign

0.15

T;T;T

Polyphen

0.0010

B;.;B

Vest4

0.094

MutPred

0.17

Gain of glycosylation at P105 (P = 0.2005);.;.;

MVP

0.60

MPC

0.12

ClinPred

0.46

GERP RS

4.4

Varity_R

0.14

gMVP

0.42

Mutation Taster

=76/24

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.76

dbscSNV1_RF

Benign

0.45

SpliceAI score (max)

0.040

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over