3-50271009-G-C

Variant summary

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

The NM_001290060.2(SEMA3B):c.450G>C(p.Glu150Asp) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000691 in 1,447,458 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 (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SEMA3B NM_001290060.2 missense, splice_region
• Scores: Splicing: ADA: 0.9861
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.60

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/exons	MANE	UniProt
SEMA3B	NM_001290060.2	c.450G>C	p.Glu150Asp	missense_variant, splice_region_variant	4/17	ENST00000616701.5
SEMA3B	NM_001290061.1	c.450G>C	p.Glu150Asp	missense_variant, splice_region_variant	4/17
SEMA3B	NM_004636.4	c.450G>C	p.Glu150Asp	missense_variant, splice_region_variant	5/18
SEMA3B	NM_001005914.3	c.450G>C	p.Glu150Asp	missense_variant, splice_region_variant	5/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SEMA3B	ENST00000616701.5	c.450G>C	p.Glu150Asp	missense_variant, splice_region_variant	4/17	1	NM_001290060.2	P5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.91e-7 AC: 1 AN: 1447458 Hom.: 0 Cov.: 32 AF XY: 0.00000139 AC XY: 1 AN XY: 718656

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: 0.0000119

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Neurodevelopmental disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Jan 01, 2019

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.011	T
BayesDel_noAF	Benign	-0.25
CADD	Uncertain	25
DANN	Benign	0.74
Eigen	Benign	-0.049
Eigen_PC	Benign	0.072
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.77	T;T;.;T;T
MetaRNN	Benign	0.24	T;T;T;T;T
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.37	T
Sift4G	Benign	0.074	T;D;D;D;D
Polyphen		0.0	.;B;B;B;.
Vest4		0.25, 0.25, 0.25, 0.25
MutPred		0.49		Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);
MVP		0.31
ClinPred		0.90	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.19
gMVP		0.72

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Benign	0.67
SpliceAI score (max)		0.50		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.50		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1701032174; hg19: chr3-50308440;