rs2231801

chr14-23360281-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_005864.4(EFS):c.298G>A(p.Val100Met) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0158 in 1,607,374 control chromosomes in the GnomAD database, including 249 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/23 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. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.011 (14 hom., cov: 32)
  • Exomes 𝑓: 0.016 (235 hom.)
• Consequence: EFS NM_005864.4 missense, splice_region
• Scores: Splicing: ADA: 0.8433
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.73

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007813156).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0112 (1700/152154) while in subpopulation NFE AF= 0.0194 (1317/67994). AF 95% confidence interval is 0.0185. There are 14 homozygotes in gnomad4. There are 737 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EFS	NM_005864.4	c.298G>A	p.Val100Met	missense_variant, splice_region_variant	3/6	ENST00000216733.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EFS	ENST00000216733.8	c.298G>A	p.Val100Met	missense_variant, splice_region_variant	3/6	1	NM_005864.4	P1
EFS	ENST00000351354.3	c.19G>A	p.Val7Met	missense_variant, splice_region_variant	2/5	1
EFS	ENST00000429593.6	c.19G>A	p.Val7Met	missense_variant, splice_region_variant	2/6	2

Frequencies

GnomAD3 genomes AF: 0.0112 AC: 1701 AN: 152036 Hom.: 14 Cov.: 32

Gnomad AFR AF: 0.00324

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.00459

Gnomad ASJ AF: 0.00721

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.0109

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0194

Gnomad OTH AF: 0.00862

GnomAD3 exomes AF: 0.0115 AC: 2796 AN: 242864 Hom.: 23 AF XY: 0.0115 AC XY: 1514 AN XY: 131232

Gnomad AFR exome AF: 0.00236

Gnomad AMR exome AF: 0.00268

Gnomad ASJ exome AF: 0.00822

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00172

Gnomad FIN exome AF: 0.0136

Gnomad NFE exome AF: 0.0201

Gnomad OTH exome AF: 0.0107

GnomAD4 exome AF: 0.0163 AC: 23662 AN: 1455220 Hom.: 235 Cov.: 35 AF XY: 0.0158 AC XY: 11430 AN XY: 723550

Gnomad4 AFR exome AF: 0.00207

Gnomad4 AMR exome AF: 0.00256

Gnomad4 ASJ exome AF: 0.00811

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00182

Gnomad4 FIN exome AF: 0.0147

Gnomad4 NFE exome AF: 0.0195

Gnomad4 OTH exome AF: 0.0127

GnomAD4 genome AF: 0.0112 AC: 1700 AN: 152154 Hom.: 14 Cov.: 32 AF XY: 0.00991 AC XY: 737 AN XY: 74386

Gnomad4 AFR AF: 0.00323

Gnomad4 AMR AF: 0.00458

Gnomad4 ASJ AF: 0.00721

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00207

Gnomad4 FIN AF: 0.0109

Gnomad4 NFE AF: 0.0194

Gnomad4 OTH AF: 0.00853

Alfa AF: 0.0167 Hom.: 55

Bravo AF: 0.00994

TwinsUK AF: 0.0170 AC: 63

ALSPAC AF: 0.0195 AC: 75

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.0199 AC: 171

ExAC AF: 0.0120 AC: 1460

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.36
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.078	T;.;.
Eigen	Benign	0.11
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.80	T;T;T
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.0071	T;T;T
MetaSVM	Benign	-0.57	T
MutationAssessor	Uncertain	2.3	M;.;.
MutationTaster	Benign	0.55	D;D;N
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.6	N;N;N
REVEL	Benign	0.094
Sift	Uncertain	0.0040	D;D;D
Sift4G	Uncertain	0.018	D;D;D
Polyphen		0.66	P;.;P
Vest4		0.33
MPC		0.41
ClinPred		0.013	T
GERP RS		4.4
Varity_R		0.14
gMVP		0.48

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.84
dbscSNV1_RF	Benign	0.47
SpliceAI score (max)		0.010		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: rs2231801; hg19: chr14-23829490; COSMIC: COSV53732398; COSMIC: COSV53732398;