rs1046999200

Variant names:

• chr14-23357238-G-C
• rs1046999200
• NM_005864.4:c.1674C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005864.4(EFS):​c.1674C>G​(p.Ser558Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000323 in 1,550,380 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: EFS NM_005864.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.472
• 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]

ENSG00000259018 (HGNC:):

ACMG classification

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=0.17502058).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EFS	NM_005864.4	c.1674C>G	p.Ser558Arg	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.1674C>G	p.Ser558Arg	missense_variant	Exon 6 of 6	1	NM_005864.4	ENSP00000216733.3
EFS	ENST00000351354.3	c.1395C>G	p.Ser465Arg	missense_variant	Exon 5 of 5	1		ENSP00000340607.3
EFS	ENST00000429593.6	c.1167C>G	p.Ser389Arg	missense_variant	Exon 6 of 6	2		ENSP00000416684.2
ENSG00000259018	ENST00000554010.1	n.*235G>C		downstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152208 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 7.15e-7 AC: 1 AN: 1398172 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 685692

African (AFR) AF: 0.0000309 AC: 1 AN: 32368

American (AMR) AF: 0.00 AC: 0 AN: 40642

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22652

East Asian (EAS) AF: 0.00 AC: 0 AN: 38644

South Asian (SAS) AF: 0.00 AC: 0 AN: 76946

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51432

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5458

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1072490

Other (OTH) AF: 0.00 AC: 0 AN: 57540

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152208 Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4 AN XY: 74362

African (AFR) AF: 0.0000965 AC: 4 AN: 41462

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 17, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1674C>G (p.S558R) alteration is located in exon 6 (coding exon 6) of the EFS gene. This alteration results from a C to G substitution at nucleotide position 1674, causing the serine (S) at amino acid position 558 to be replaced by an arginine (R). 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	0.21
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	16
DANN	Benign	0.97
DEOGEN2	Benign	0.039	T;.;.
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.22
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.79	T;T;T
M_CAP	Benign	0.0094	T
MetaRNN	Benign	0.18	T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.9	L;.;.
PhyloP100		0.47
PrimateAI	Benign	0.42	T
PROVEAN	Benign	0.16	N;N;N
REVEL	Benign	0.040
Sift	Uncertain	0.022	D;T;T
Sift4G	Benign	0.84	T;T;T
Polyphen		0.0030	B;.;P
Vest4		0.10
MutPred		0.20		Loss of glycosylation at S558 (P = 0.0233);.;.;
MVP		0.74
MPC		0.28
ClinPred		0.11	T
GERP RS		0.70
Varity_R		0.075
gMVP		0.16
Mutation Taster		=83/17	polymorphism

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: rs1046999200; hg19: chr14-23826447;