chr14-23359450-C-T

Variant names:

• chr14-23359450-C-T
• rs753502762
• NM_005864.4:c.1028G>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_005864.4(EFS):​c.1028G>A​(p.Arg343His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000659 in 515,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict 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. R343C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000018 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000079 (0 hom.)
• Consequence: EFS NM_005864.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0130

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

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.047722876).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EFS	NM_005864.4	c.1028G>A	p.Arg343His	missense_variant	Exon 4 of 6	ENST00000216733.8	NP_005855.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EFS	ENST00000216733.8	c.1028G>A	p.Arg343His	missense_variant	Exon 4 of 6	1	NM_005864.4	ENSP00000216733.3
EFS	ENST00000351354.3	c.749G>A	p.Arg250His	missense_variant	Exon 3 of 5	1		ENSP00000340607.3
EFS	ENST00000429593.6	c.521G>A	p.Arg174His	missense_variant	Exon 4 of 6	2		ENSP00000416684.2

Frequencies

GnomAD3 genomes AF: 0.0000179 AC: 2 AN: 111628 Hom.: 0 Cov.: 30

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: 0.000338

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000196

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000481 AC: 9 AN: 187276 Hom.: 0 AF XY: 0.0000478 AC XY: 5 AN XY: 104608

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000504

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000826

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000675

Gnomad OTH exome AF: 0.000243

GnomAD4 exome AF: 0.0000792 AC: 32 AN: 404264 Hom.: 0 Cov.: 24 AF XY: 0.0000919 AC XY: 20 AN XY: 217592

Gnomad4 AFR exome AF: 0.000194

Gnomad4 AMR exome AF: 0.0000972

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000120

Gnomad4 SAS exome AF: 0.000174

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000485

Gnomad4 OTH exome AF: 0.000259

GnomAD4 genome AF: 0.0000179 AC: 2 AN: 111628 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 54990

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000338

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000196

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000334 Hom.: 0

ExAC AF: 0.0000503 AC: 6

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 14, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1028G>A (p.R343H) alteration is located in exon 4 (coding exon 4) of the EFS gene. This alteration results from a G to A substitution at nucleotide position 1028, causing the arginine (R) at amino acid position 343 to be replaced by a histidine (H). 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	0.069
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	16
DANN	Benign	0.79
DEOGEN2	Benign	0.048	T;.;.
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.29
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.78	T;T;T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.048	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.55	N;.;.
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.56	N;N;N
REVEL	Benign	0.027
Sift	Benign	0.54	T;T;T
Sift4G	Benign	0.19	T;T;T
Polyphen		0.022	B;.;B
Vest4		0.097
MutPred		0.28		Loss of methylation at R343 (P = 0.0388);.;.;
MVP		0.62
MPC		0.14
ClinPred		0.041	T
GERP RS		3.8
Varity_R		0.037
gMVP		0.35

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

LitVar

Other links and lift over

dbSNP: rs753502762; hg19: chr14-23828659; COSMIC: COSV53733823; COSMIC: COSV53733823;