3-122912930-A-C

Position:

• chr3-122912930-A-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001031702.4(SEMA5B):​c.2638T>G​(p.Cys880Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,460,628 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: SEMA5B NM_001031702.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.29

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]

SEMA5B (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.964

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SEMA5B	NM_001031702.4	c.2638T>G	p.Cys880Gly	missense_variant	18/23	ENST00000357599.8	NP_001026872.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SEMA5B	ENST00000357599.8	c.2638T>G	p.Cys880Gly	missense_variant	18/23	1	NM_001031702.4	ENSP00000350215.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1460628 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 726596

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000630

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 05, 2023

The c.2638T>G (p.C880G) alteration is located in exon 18 (coding exon 17) of the SEMA5B gene. This alteration results from a T to G substitution at nucleotide position 2638, causing the cysteine (C) at amino acid position 880 to be replaced by a glycine (G). 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	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	29
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.48	.;.;T;.;T;.;T
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.90	D;D;D;D;.;D;D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D;D;D
MetaSVM	Uncertain	0.72	D
MutationAssessor	Pathogenic	3.8	.;.;H;.;H;.;.
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-10	.;D;.;.;D;.;D
REVEL	Pathogenic	0.75
Sift	Uncertain	0.0050	.;D;.;.;D;.;D
Sift4G	Pathogenic	0.0	.;D;D;D;D;.;D
Polyphen		1.0	.;.;D;.;D;.;.
Vest4		0.98, 0.98, 0.98, 0.97
MutPred		0.79		.;.;Gain of glycosylation at T881 (P = 0.0136);.;Gain of glycosylation at T881 (P = 0.0136);.;Gain of glycosylation at T881 (P = 0.0136);
MVP		0.96
MPC		1.1
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.98
gMVP		0.96

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: rs1261615705; hg19: chr3-122631777;