Genetic Variant SEMA5B:p.Cys880Phe (chr3-122912929-C-A) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_001031702.4(SEMA5B):c.2639G>T(p.Cys880Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,606 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C880G) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

SEMA5B
NM_001031702.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.88

Variant links:

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 links:

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ACMG classification

Classification made for transcript

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, 0.958

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SEMA5B	NM_001031702.4 link	c.2639G>T	p.Cys880Phe	missense_variant	Exon 18 of 23	ENST00000357599.8	NP_001026872.2	Q9P283-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SEMA5B	ENST00000357599.8 link	c.2639G>T	p.Cys880Phe	missense_variant	Exon 18 of 23	1	NM_001031702.4	ENSP00000350215.3		Q9P283-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000406

AC:

AN:

246016

Hom.:

AF XY:

0.00000748

AC XY:

AN XY:

133768

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000291

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1460606

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726572

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

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:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 22, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2639G>T (p.C880F) alteration is located in exon 18 (coding exon 17) of the SEMA5B gene. This alteration results from a G to T substitution at nucleotide position 2639, causing the cysteine (C) at amino acid position 880 to be replaced by a phenylalanine (F). 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

0.98

BayesDel_addAF

Pathogenic

0.34

BayesDel_noAF

Pathogenic

0.34

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.40

.;.;T;.;T;.;T

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.91

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.97

D;D;D;D;.;D;D

M_CAP

Pathogenic

0.30

MetaRNN

Pathogenic

0.96

D;D;D;D;D;D;D

MetaSVM

Uncertain

0.70

MutationAssessor

Pathogenic

3.9

.;.;H;.;H;.;.

PrimateAI

Uncertain

0.79

PROVEAN

Pathogenic

-9.6

.;D;.;.;D;.;D

REVEL

Pathogenic

0.78

Sift

Uncertain

0.0010

.;D;.;.;D;.;D

Sift4G

Uncertain

0.0030

.;D;D;D;D;.;D

Polyphen

1.0

.;.;D;.;D;.;.

Vest4

0.98, 0.97, 0.96, 0.97

MutPred

0.76

.;.;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

0.94

MPC

1.2

ClinPred

1.0

GERP RS

5.0

Varity_R

0.99

gMVP

0.95

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over