15-47760398-A-C

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The NM_001358351.3(SEMA6D):c.204A>C(p.Thr68=) 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 (★).

• Frequency:
  • Genomes: 𝑓 0.074 (1254 hom., cov: 33)
  • Exomes 𝑓: 0.014 (1676 hom.)
• Consequence: SEMA6D NM_001358351.3 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.02

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]

ACMG classification

Verdict is Benign. Variant got -15 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 criteria_provided_single_submitter, 1 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/exons	MANE	UniProt
SEMA6D	NM_001358351.3	c.204A>C	p.Thr68=	synonymous_variant	3/19	ENST00000536845.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SEMA6D	ENST00000536845.7	c.204A>C	p.Thr68=	synonymous_variant	3/19	2	NM_001358351.3	P4

Frequencies

GnomAD3 genomes AF: 0.0736 AC: 11193 AN: 152088 Hom.: 1244 Cov.: 33

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

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.: 30 AF XY: 0.0151 AC XY: 10985 AN XY: 726726

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.: 33 AF XY: 0.0727 AC XY: 5412 AN XY: 74396

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: criteria provided, single submitter

Submissions by phenotype

SEMA6D-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 14, 2020

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	12
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

Other links and lift over

dbSNP: rs1866501; hg19: chr15-48052595; COSMIC: COSV60384675; COSMIC: COSV60384675;