14-23357621-C-A

Variant names:

• chr14-23357621-C-A
• rs780224177
• NM_005864.4:c.1291G>T

Variant summary

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

The NM_005864.4(EFS):​c.1291G>T​(p.Gly431*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: EFS NM_005864.4 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.18
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EFS	NM_005864.4	c.1291G>T	p.Gly431*	stop_gained	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.1291G>T	p.Gly431*	stop_gained	Exon 6 of 6	1	NM_005864.4	ENSP00000216733.3
EFS	ENST00000351354.3	c.1012G>T	p.Gly338*	stop_gained	Exon 5 of 5	1		ENSP00000340607.3
EFS	ENST00000429593.6	c.784G>T	p.Gly262*	stop_gained	Exon 6 of 6	2		ENSP00000416684.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1406676 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 690836

African (AFR) AF: 0.00 AC: 0 AN: 32516

American (AMR) AF: 0.00 AC: 0 AN: 41874

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23172

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 78336

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51722

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5446

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1077106

Other (OTH) AF: 0.00 AC: 0 AN: 57860

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	37
DANN	Uncertain	0.99
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.93	D
PhyloP100		1.2
Vest4		0.70
GERP RS		3.8
Mutation Taster		=22/178	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.21		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.21		Position offset: 39

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs780224177; hg19: chr14-23826830;