3-50270957-C-T

Variant names:

• chr3-50270957-C-T
• rs367658577
• NM_001290060.2:c.398C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The NM_001290060.2(SEMA3B):​c.398C>T​(p.Thr133Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000515 in 1,611,248 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 (no stars).

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000029 (0 hom.)
• Consequence: SEMA3B NM_001290060.2 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 6.12

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

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.751

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SEMA3B	NM_001290060.2	c.398C>T	p.Thr133Met	missense_variant	Exon 4 of 17	ENST00000616701.5	NP_001276989.1
SEMA3B	NM_001290061.1	c.398C>T	p.Thr133Met	missense_variant	Exon 4 of 17		NP_001276990.1
SEMA3B	NM_004636.4	c.398C>T	p.Thr133Met	missense_variant	Exon 5 of 18		NP_004627.1
SEMA3B	NM_001005914.3	c.398C>T	p.Thr133Met	missense_variant	Exon 5 of 18		NP_001005914.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SEMA3B	ENST00000616701.5	c.398C>T	p.Thr133Met	missense_variant	Exon 4 of 17	1	NM_001290060.2	ENSP00000484146.1

Frequencies

GnomAD3 genomes AF: 0.000263 AC: 40 AN: 152102 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000918

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: 0.00

Gnomad OTH AF: 0.000960

GnomAD2 exomes AF: 0.0000492 AC: 12 AN: 243952 AF XY: 0.0000604

Gnomad AFR exome AF: 0.000401

Gnomad AMR exome AF: 0.000118

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000905

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000295 AC: 43 AN: 1459146 Hom.: 0 Cov.: 32 AF XY: 0.0000331 AC XY: 24 AN XY: 725558

Gnomad4 AFR exome AF: 0.000568 AC: 19 AN: 33448

Gnomad4 AMR exome AF: 0.0000676 AC: 3 AN: 44350

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26078

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39628

Gnomad4 SAS exome AF: 0.0000117 AC: 1 AN: 85530

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53232

Gnomad4 NFE exome AF: 0.0000135 AC: 15 AN: 1110808

Gnomad4 Remaining exome AF: 0.0000829 AC: 5 AN: 60306

GnomAD4 genome AF: 0.000263 AC: 40 AN: 152102 Hom.: 0 Cov.: 33 AF XY: 0.000256 AC XY: 19 AN XY: 74302

Gnomad4 AFR AF: 0.000918 AC: 0.000918052 AN: 0.000918052

Gnomad4 AMR AF: 0.00 AC: 0 AN: 0

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.00 AC: 0 AN: 0

Gnomad4 OTH AF: 0.000960 AC: 0.000959693 AN: 0.000959693

Alfa AF: 0.000329 Hom.: 0

Bravo AF: 0.000336

ESP6500AA AF: 0.000718 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000744 AC: 9

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

SEMA3B-related disorder Uncertain:1

May 15, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The SEMA3B c.398C>T variant is predicted to result in the amino acid substitution p.Thr133Met. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.063% of alleles in individuals of African descent in gnomAD, which may be too common to be a primary cause of disease. Although we suspect that this variant may be benign, 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	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	31
DANN	Uncertain	0.98
DEOGEN2	Benign	0.38	.;T;T;.;.
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	0.98	D;D;.;D;D
MetaRNN	Pathogenic	0.75	D;D;D;D;D
MetaSVM	Uncertain	0.010	D
PrimateAI	Uncertain	0.78	T
Sift4G	Pathogenic	0.0010	D;D;D;D;D
Polyphen		1.0	.;D;D;D;.
Vest4		0.91, 0.91
MVP		0.59
ClinPred		0.93	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.47
gMVP		0.96
Mutation Taster		=93/7	polymorphism

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: rs367658577; hg19: chr3-50308388;