rs562816221

Variant names:

• chr14-23357453-C-A
• rs562816221
• NM_005864.4:c.1459G>T

Your query was ambiguous. Multiple possible variants found:

• chr14-23357453-C-A
• chr14-23357453-C-G

Variant summary

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

The NM_005864.4(EFS):​c.1459G>T​(p.Val487Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000942 in 1,613,920 control chromosomes in the GnomAD database, including 2 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. V487A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00012 (1 hom., cov: 33)
  • Exomes 𝑓: 0.000091 (1 hom.)
• Consequence: EFS NM_005864.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.85
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06887257).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EFS	NM_005864.4	c.1459G>T	p.Val487Phe	missense_variant	Exon 6 of 6	ENST00000216733.8	NP_005855.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EFS	ENST00000216733.8	c.1459G>T	p.Val487Phe	missense_variant	Exon 6 of 6	1	NM_005864.4	ENSP00000216733.3
EFS	ENST00000351354.3	c.1180G>T	p.Val394Phe	missense_variant	Exon 5 of 5	1		ENSP00000340607.3
EFS	ENST00000429593.6	c.952G>T	p.Val318Phe	missense_variant	Exon 6 of 6	2		ENSP00000416684.2

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152256 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00310

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000176 AC: 44 AN: 250358 AF XY: 0.000207

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: 0.0000354

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000910 AC: 133 AN: 1461546 Hom.: 1 Cov.: 30 AF XY: 0.000129 AC XY: 94 AN XY: 727078

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00126 AC: 109 AN: 86222

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53250

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5728

European-Non Finnish (NFE) AF: 0.0000180 AC: 20 AN: 1111950

Other (OTH) AF: 0.0000662 AC: 4 AN: 60380

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152374 Hom.: 1 Cov.: 33 AF XY: 0.000188 AC XY: 14 AN XY: 74512

African (AFR) AF: 0.0000481 AC: 2 AN: 41596

American (AMR) AF: 0.00 AC: 0 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00310 AC: 15 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.0000688 Hom.: 0

Bravo AF: 0.0000567

ExAC AF: 0.000181 AC: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 27, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1459G>T (p.V487F) 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 1459, causing the valine (V) at amino acid position 487 to be replaced by a phenylalanine (F). 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	Uncertain	0.49
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T;.;.
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.069	T;T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Uncertain	2.8	M;.;.
PhyloP100		1.9
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-3.2	D;D;D
REVEL	Benign	0.22
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.0080	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.75
MVP		0.45
MPC		0.63
ClinPred		0.27	T
GERP RS		3.8
Varity_R		0.64
gMVP		0.61
Mutation Taster		=39/61	disease causing

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

Other links and lift over

dbSNP: rs562816221; hg19: chr14-23826662;