chr7-80745026-A-C

Variant names:

• chr7-80745026-A-C
• rs1949971
• NM_006379.5:c.2124T>G

Variant summary

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

The NM_006379.5(SEMA3C):​c.2124T>G​(p.Tyr708*) 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. Synonymous variant affecting the same amino acid position (i.e. Y708Y) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SEMA3C NM_006379.5 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.77
• Publications: 19 publications found

Genes affected

SEMA3C (HGNC:10725): (semaphorin 3C) This gene encodes a secreted glycoprotein that belongs to the semaphorin class 3 family of neuronal guidance cues. The encoded protein contains an N-terminal sema domain, integrin and immunoglobulin-like domains, and a C-terminal basic domain. Homodimerization and proteolytic cleavage of the C-terminal propeptide are necessary for the function of the encoded protein. It binds a neuropilin co-receptor before forming a heterotrimeric complex with an associated plexin. An increase in the expression of this gene correlates with an increase in cancer cell invasion and adhesion. Naturally occurring mutations in this gene are associated with Hirschsprung disease. [provided by RefSeq, May 2017]

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
SEMA3C	NM_006379.5	c.2124T>G	p.Tyr708*	stop_gained	Exon 18 of 18	ENST00000265361.8	NP_006370.1
SEMA3C	NM_001350120.2	c.2178T>G	p.Tyr726*	stop_gained	Exon 18 of 18		NP_001337049.1
SEMA3C	NM_001350121.2	c.1950T>G	p.Tyr650*	stop_gained	Exon 19 of 19		NP_001337050.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SEMA3C	ENST00000265361.8	c.2124T>G	p.Tyr708*	stop_gained	Exon 18 of 18	1	NM_006379.5	ENSP00000265361.3
SEMA3C	ENST00000419255.6	c.2124T>G	p.Tyr708*	stop_gained	Exon 18 of 18	2		ENSP00000411193.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 68

GnomAD4 genome Cov.: 32

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	38
DANN	Uncertain	1.0
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.91	D
PhyloP100		2.8
Vest4		0.76
GERP RS		3.6
Mutation Taster		=7/193	disease causing

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: rs1949971; hg19: chr7-80374342;