14-23360281-C-T

Variant names:

• chr14-23360281-C-T
• rs2231801
• NM_005864.4:c.298G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting 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. 16/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as (no stars).

• 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
• Publications: 8 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: Benign. The variant received -9 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 14 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005864.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EFS	NM_005864.4	MANE Select	c.298G>A	p.Val100Met	missense splice_region	Exon 3 of 6	NP_005855.1	O43281-1
	EFS	NM_032459.3		c.19G>A	p.Val7Met	missense splice_region	Exon 2 of 5	NP_115835.1	O43281-2
	EFS	NM_001385607.1		c.19G>A	p.Val7Met	missense splice_region	Exon 2 of 4	NP_001372536.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EFS	ENST00000216733.8	TSL:1 MANE Select	c.298G>A	p.Val100Met	missense splice_region	Exon 3 of 6	ENSP00000216733.3	O43281-1
	EFS	ENST00000351354.3	TSL:1	c.19G>A	p.Val7Met	missense splice_region	Exon 2 of 5	ENSP00000340607.3	O43281-2
	EFS	ENST00000923553.1		c.298G>A	p.Val100Met	missense splice_region	Exon 3 of 5	ENSP00000593612.1

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

GnomAD2 exomes AF: 0.0115 AC: 2796 AN: 242864 AF XY: 0.0115

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 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

African (AFR) AF: 0.00207 AC: 69 AN: 33270

American (AMR) AF: 0.00256 AC: 112 AN: 43730

Ashkenazi Jewish (ASJ) AF: 0.00811 AC: 207 AN: 25526

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39642

South Asian (SAS) AF: 0.00182 AC: 155 AN: 85338

European-Finnish (FIN) AF: 0.0147 AC: 776 AN: 52958

Middle Eastern (MID) AF: 0.00140 AC: 8 AN: 5720

European-Non Finnish (NFE) AF: 0.0195 AC: 21571 AN: 1108996

Other (OTH) AF: 0.0127 AC: 763 AN: 60040

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

African (AFR) AF: 0.00323 AC: 134 AN: 41520

American (AMR) AF: 0.00458 AC: 70 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00721 AC: 25 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5152

South Asian (SAS) AF: 0.00207 AC: 10 AN: 4832

European-Finnish (FIN) AF: 0.0109 AC: 116 AN: 10598

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

European-Non Finnish (NFE) AF: 0.0194 AC: 1317 AN: 67994

Other (OTH) AF: 0.00853 AC: 18 AN: 2110

Alfa AF: 0.0154 Hom.: 67

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 v4.9

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
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.0071	T
MetaSVM	Benign	-0.57	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		1.7
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.094
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.018	D
Polyphen		0.66	P
Vest4		0.33
MPC		0.41
ClinPred		0.013	T
GERP RS		4.4
Varity_R		0.14
gMVP		0.48
Mutation Taster		=76/24	polymorphism

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

Other links and lift over

dbSNP: rs2231801; hg19: chr14-23829490; COSMIC: COSV53732398; COSMIC: COSV53732398;