3-50269251-C-A

Variant names:

• chr3-50269251-C-A
• rs587728978
• NM_001290060.2:c.11C>A

Variant summary

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

The NM_001290060.2(SEMA3B):​c.11C>A​(p.Ala4Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SEMA3B NM_001290060.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.76

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SEMA3B	NM_001290060.2	c.11C>A	p.Ala4Asp	missense_variant	Exon 1 of 17	ENST00000616701.5	NP_001276989.1
SEMA3B	NM_001290061.1	c.11C>A	p.Ala4Asp	missense_variant	Exon 1 of 17		NP_001276990.1
SEMA3B	NM_004636.4	c.11C>A	p.Ala4Asp	missense_variant	Exon 2 of 18		NP_004627.1
SEMA3B	NM_001005914.3	c.11C>A	p.Ala4Asp	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.11C>A	p.Ala4Asp	missense_variant	Exon 1 of 17	1	NM_001290060.2	ENSP00000484146.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1383924 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 683078

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 09, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.11C>A (p.A4D) alteration is located in exon 2 (coding exon 1) of the SEMA3B gene. This alteration results from a C to A substitution at nucleotide position 11, causing the alanine (A) at amino acid position 4 to be replaced by an aspartic acid (D). 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	Benign	0.17
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Benign	18
DANN	Benign	0.67
DEOGEN2	Benign	0.073	.;T;T;.;.
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.70	T;T;.;T;T
MetaRNN	Uncertain	0.50	T;T;T;T;T
MetaSVM	Benign	-0.96	T
PrimateAI	Uncertain	0.72	T
Sift4G	Benign	0.086	T;T;T;T;T
Polyphen		0.0	.;B;B;.;.
Vest4		0.65, 0.62, 0.64, 0.73
MutPred		0.62		Gain of relative solvent accessibility (P = 0.0479);Gain of relative solvent accessibility (P = 0.0479);Gain of relative solvent accessibility (P = 0.0479);Gain of relative solvent accessibility (P = 0.0479);Gain of relative solvent accessibility (P = 0.0479);
MVP		0.43
ClinPred		0.72	D
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.16
gMVP		0.74

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: rs587728978; hg19: chr3-50306683;