rs267607034

Variant names:

• chr1-156163009-T-G
• rs267607034
• NM_022367.4:c.1049T>G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_022367.4(SEMA4A):​c.1049T>G​(p.Phe350Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. F350F) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SEMA4A NM_022367.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 7.22

Genes affected

SEMA4A (HGNC:10729): (semaphorin 4A) This gene encodes a member of the semaphorin family of soluble and transmembrane proteins. Semaphorins are involved in numerous functions, including axon guidance, morphogenesis, carcinogenesis, and immunomodulation. The encoded protein is a single-pass type I membrane protein containing an immunoglobulin-like C2-type domain, a PSI domain and a sema domain. It inhibits axonal extension by providing local signals to specify territories inaccessible for growing axons. It is an activator of T-cell-mediated immunity and suppresses vascular endothelial growth factor (VEGF)-mediated endothelial cell migration and proliferation in vitro and angiogenesis in vivo. Mutations in this gene are associated with retinal degenerative diseases including retinitis pigmentosa type 35 (RP35) and cone-rod dystrophy type 10 (CORD10). Multiple alternatively spliced transcript variants encoding different isoforms have been identified.[provided by RefSeq, Sep 2010]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99
• PP5: Variant 1-156163009-T-G is Pathogenic according to our data. Variant chr1-156163009-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 3361.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-156163009-T-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SEMA4A	NM_022367.4	c.1049T>G	p.Phe350Cys	missense_variant	Exon 10 of 15	ENST00000368285.8	NP_071762.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SEMA4A	ENST00000368285.8	c.1049T>G	p.Phe350Cys	missense_variant	Exon 10 of 15	1	NM_022367.4	ENSP00000357268.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Retinitis pigmentosa 35 Pathogenic:1

Jan 01, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Cone-rod dystrophy 10 Pathogenic:1

Jan 01, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.49	T;T;.;T;T
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.84	.;.;T;T;T
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Uncertain	0.071	D
MutationAssessor	Pathogenic	3.6	H;H;.;.;H
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-7.1	D;D;D;.;D
REVEL	Pathogenic	0.72
Sift	Pathogenic	0.0	D;D;D;.;D
Sift4G	Uncertain	0.0020	D;D;D;D;D
Polyphen		1.0	D;D;.;.;D
Vest4		0.97
MutPred		0.98		Gain of methylation at K351 (P = 0.0296);Gain of methylation at K351 (P = 0.0296);.;.;Gain of methylation at K351 (P = 0.0296);
MVP		0.90
MPC		0.83
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.93
gMVP		0.90

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

Publications

LitVar

Other links and lift over

dbSNP: rs267607034; hg19: chr1-156132800;