3-122911515-T-C

Position:

• chr3-122911515-T-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_001031702.4(SEMA5B):​c.3067A>G​(p.Met1023Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,458,152 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SEMA5B NM_001031702.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.578

Genes affected

SEMA5B (HGNC:10737): (semaphorin 5B) This gene encodes a member of the semaphorin protein family which regulates axon growth during development of the nervous system. The encoded protein has a characteristic Sema domain near the N-terminus, through which semaphorins bind to plexin, and five thrombospondin type 1 repeats in the C-terminal region of the protein. The protein product may be cleaved and exist as a secreted molecule (PMID: 19463192). Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2012]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.031582475).
• BP6: Variant 3-122911515-T-C is Benign according to our data. Variant chr3-122911515-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 2245642.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SEMA5B	NM_001031702.4	c.3067A>G	p.Met1023Val	missense_variant	21/23	ENST00000357599.8	NP_001026872.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SEMA5B	ENST00000357599.8	c.3067A>G	p.Met1023Val	missense_variant	21/23	1	NM_001031702.4	ENSP00000350215

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1458152 Hom.: 0 Cov.: 35 AF XY: 0.00000276 AC XY: 2 AN XY: 724816

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000118

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 16, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	9.7
DANN	Benign	0.57
DEOGEN2	Benign	0.021	.;.;T;.;T;.;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.35	N
LIST_S2	Benign	0.73	T;T;T;T;.;T;T
M_CAP	Benign	0.0022	T
MetaRNN	Benign	0.032	T;T;T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.34	.;.;N;.;N;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	0.27	.;N;.;.;N;.;N
REVEL	Benign	0.025
Sift	Benign	0.63	.;T;.;.;T;.;T
Sift4G	Benign	0.75	.;T;T;T;T;.;T
Polyphen		0.0	.;.;B;.;B;.;.
Vest4		0.037, 0.031, 0.066, 0.034
MutPred		0.43		.;.;Gain of glycosylation at S1022 (P = 0.0444);.;Gain of glycosylation at S1022 (P = 0.0444);.;Gain of glycosylation at S1022 (P = 0.0444);
MVP		0.38
MPC		0.27
ClinPred		0.041	T
GERP RS		-2.2
Varity_R		0.042
gMVP		0.20

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: rs906193478; hg19: chr3-122630362;