3-50269329-G-A

Variant names:

• chr3-50269329-G-A
• rs587618842
• NM_001290060.2:c.89G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001290060.2(SEMA3B):​c.89G>A​(p.Arg30His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000146 in 1,511,502 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R30C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: SEMA3B NM_001290060.2 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 0.351

Genes affected

SEMA3B (HGNC:10724): (semaphorin 3B) The protein encoded by this gene belongs to the class-3 semaphorin/collapsin family, whose members function in growth cone guidance during neuronal development. This family member inhibits axonal extension and has been shown to act as a tumor suppressor by inducing apoptosis. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Feb 2014]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15999877).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SEMA3B	NM_001290060.2	c.89G>A	p.Arg30His	missense_variant	Exon 1 of 17	ENST00000616701.5	NP_001276989.1
SEMA3B	NM_001290061.1	c.89G>A	p.Arg30His	missense_variant	Exon 1 of 17		NP_001276990.1
SEMA3B	NM_004636.4	c.89G>A	p.Arg30His	missense_variant	Exon 2 of 18		NP_004627.1
SEMA3B	NM_001005914.3	c.89G>A	p.Arg30His	missense_variant	Exon 2 of 18		NP_001005914.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SEMA3B	ENST00000616701.5	c.89G>A	p.Arg30His	missense_variant	Exon 1 of 17	1	NM_001290060.2	ENSP00000484146.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152082 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000922 AC: 1 AN: 108430 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 59598

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000621

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: 0.0000147 AC: 20 AN: 1359302 Hom.: 0 Cov.: 30 AF XY: 0.00000895 AC XY: 6 AN XY: 670254

Gnomad4 AFR exome AF: 0.0000337

Gnomad4 AMR exome AF: 0.0000367

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000847

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000141

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152200 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74420

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

SEMA3B-related disorder Uncertain:1

Jul 05, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The SEMA3B c.89G>A variant is predicted to result in the amino acid substitution p.Arg30His. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0062% of alleles in individuals of Latino descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Benign	-0.053	T
BayesDel_noAF	Benign	-0.31
CADD	Pathogenic	31
DANN	Benign	0.95
DEOGEN2	Benign	0.31	.;T;T;.;.
Eigen	Uncertain	0.22
Eigen_PC	Benign	0.16
FATHMM_MKL	Benign	0.41	N
LIST_S2	Uncertain	0.90	D;D;.;D;D
MetaRNN	Benign	0.16	T;T;T;T;T
MetaSVM	Benign	-0.43	T
PrimateAI	Uncertain	0.67	T
Sift4G	Uncertain	0.0040	D;D;D;D;D
Polyphen		1.0	.;D;D;.;.
Vest4		0.25, 0.23, 0.27, 0.34
MutPred		0.55		Loss of methylation at R30 (P = 0.0252);Loss of methylation at R30 (P = 0.0252);Loss of methylation at R30 (P = 0.0252);Loss of methylation at R30 (P = 0.0252);Loss of methylation at R30 (P = 0.0252);
MVP		0.33
ClinPred		0.69	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.13
gMVP		0.86

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: rs587618842; hg19: chr3-50306760;