Genetic Variant SEMA6D:p.Thr68Thr (chr15-47760398-A-C) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BA1

The NM_001358351.3(SEMA6D):c.204A>C(p.Thr68Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0196 in 1,612,980 control chromosomes in the GnomAD database, including 2,930 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.074 ( 1254 hom., cov: 33)

Exomes 𝑓: 0.014 ( 1676 hom. )

Consequence

SEMA6D
NM_001358351.3 synonymous

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 2.02

Variant links:

Genes affected

SEMA6D (HGNC:16770): (semaphorin 6D) Semaphorins are a large family, including both secreted and membrane associated proteins, many of which have been implicated as inhibitors or chemorepellents in axon pathfinding, fasciculation and branching, and target selection. All semaphorins possess a semaphorin (Sema) domain and a PSI domain (found in plexins, semaphorins and integrins) in the N-terminal extracellular portion. Additional sequence motifs C-terminal to the semaphorin domain allow classification into distinct subfamilies. Results demonstrate that transmembrane semaphorins, like the secreted ones, can act as repulsive axon guidance cues. This gene encodes a class 6 vertebrate transmembrane semaphorin that demonstrates alternative splicing. Several transcript variants have been identified and expression of the distinct encoded isoforms is thought to be regulated in a tissue- and development-dependent manner. [provided by RefSeq, Nov 2010]

SEMA6D links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.58).

BP6

Variant 15-47760398-A-C is Benign according to our data. Variant chr15-47760398-A-C is described in ClinVar as [Benign]. Clinvar id is 3055596.Status of the report is no_assertion_criteria_provided, 0 stars.

BP7

Synonymous conserved (PhyloP=2.02 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.235 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SEMA6D	NM_001358351.3 link	c.204A>C	p.Thr68Thr	synonymous_variant	Exon 3 of 19	ENST00000536845.7	NP_001345280.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SEMA6D	ENST00000536845.7 link	c.204A>C	p.Thr68Thr	synonymous_variant	Exon 3 of 19	2	NM_001358351.3	ENSP00000446152.3		Q8NFY4-1

Frequencies

GnomAD3 genomes

AF:

0.0736

AC:

11193

AN:

152088

Hom.:

1244

Cov.:

show subpopulations

Gnomad AFR

AF:

0.238

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0216

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0709

Gnomad SAS

AF:

0.106

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.000544

Gnomad OTH

AF:

0.0439

GnomAD3 exomes

AF:

0.0343

AC:

8598

AN:

250554

Hom.:

727

AF XY:

0.0331

AC XY:

4481

AN XY:

135420

show subpopulations

Gnomad AFR exome

AF:

0.244

Gnomad AMR exome

AF:

0.00858

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0708

Gnomad SAS exome

AF:

0.0945

Gnomad FIN exome

AF:

0.0000924

Gnomad NFE exome

AF:

0.000610

Gnomad OTH exome

AF:

0.0148

GnomAD4 exome

AF:

0.0139

AC:

20320

AN:

1460774

Hom.:

1676

Cov.:

AF XY:

0.0151

AC XY:

10985

AN XY:

726726

show subpopulations

Gnomad4 AFR exome

AF:

0.248

Gnomad4 AMR exome

AF:

0.0103

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0520

Gnomad4 SAS exome

AF:

0.0875

Gnomad4 FIN exome

AF:

0.0000375

Gnomad4 NFE exome

AF:

0.000294

Gnomad4 OTH exome

AF:

0.0264

GnomAD4 genome

AF:

0.0739

AC:

11249

AN:

152206

Hom.:

1254

Cov.:

AF XY:

0.0727

AC XY:

5412

AN XY:

74396

show subpopulations

Gnomad4 AFR

AF:

0.239

Gnomad4 AMR

AF:

0.0215

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0710

Gnomad4 SAS

AF:

0.105

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000544

Gnomad4 OTH

AF:

0.0482

Alfa

AF:

0.0293

Hom.:

309

Bravo

AF:

0.0800

Asia WGS

AF:

0.113

AC:

395

AN:

3476

EpiCase

AF:

0.000764

EpiControl

AF:

0.000830

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

SEMA6D-related disorder

Benign:1

Jan 14, 2020

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.58

CADD

Benign

DANN

Benign

0.64

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