15-47760398-A-C

Variant names:

• chr15-47760398-A-C
• rs1866501
• NM_001358351.3:c.204A>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BA1

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
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 2.02
• Publications: 3 publications found

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 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -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	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	c.204A>C	p.Thr68Thr	synonymous_variant	Exon 3 of 19	2	NM_001358351.3	ENSP00000446152.3

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

GnomAD2 exomes AF: 0.0343 AC: 8598 AN: 250554 AF XY: 0.0331

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 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

African (AFR) AF: 0.248 AC: 8279 AN: 33388

American (AMR) AF: 0.0103 AC: 458 AN: 44666

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26106

East Asian (EAS) AF: 0.0520 AC: 2061 AN: 39664

South Asian (SAS) AF: 0.0875 AC: 7539 AN: 86176

European-Finnish (FIN) AF: 0.0000375 AC: 2 AN: 53400

Middle Eastern (MID) AF: 0.0108 AC: 62 AN: 5758

European-Non Finnish (NFE) AF: 0.000294 AC: 327 AN: 1111296

Other (OTH) AF: 0.0264 AC: 1592 AN: 60320

GnomAD4 genome AF: 0.0739 AC: 11249 AN: 152206 Hom.: 1254 Cov.: 33 AF XY: 0.0727 AC XY: 5412 AN XY: 74396

African (AFR) AF: 0.239 AC: 9903 AN: 41498

American (AMR) AF: 0.0215 AC: 329 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.0710 AC: 368 AN: 5180

South Asian (SAS) AF: 0.105 AC: 507 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000544 AC: 37 AN: 68014

Other (OTH) AF: 0.0482 AC: 102 AN: 2116

Alfa AF: 0.0308 Hom.: 417

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

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	12
DANN	Benign	0.64
PhyloP100		2.0
Mutation Taster		=93/7	polymorphism (auto)

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

Other links and lift over

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