rs3743281

Variant names:

• chr15-47764761-C-T
• rs3743281
• NM_001358351.3:c.1221C>T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP7 BA1

The NM_001358351.3(SEMA6D):​c.1221C>T​(p.Ala407Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.251 in 1,613,698 control chromosomes in the GnomAD database, including 53,344 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.20 (3650 hom., cov: 33)
  • Exomes 𝑓: 0.26 (49694 hom.)
• Consequence: SEMA6D NM_001358351.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.17
• Publications: 16 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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.28).
• BP7: Synonymous conserved (PhyloP=-1.17 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.297 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SEMA6D	NM_001358351.3	c.1221C>T	p.Ala407Ala	synonymous_variant	Exon 12 of 19	ENST00000536845.7	NP_001345280.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SEMA6D	ENST00000536845.7	c.1221C>T	p.Ala407Ala	synonymous_variant	Exon 12 of 19	2	NM_001358351.3	ENSP00000446152.3

Frequencies

GnomAD3 genomes AF: 0.201 AC: 30584 AN: 152048 Hom.: 3649 Cov.: 33

Gnomad AFR AF: 0.0683

Gnomad AMI AF: 0.279

Gnomad AMR AF: 0.200

Gnomad ASJ AF: 0.223

Gnomad EAS AF: 0.186

Gnomad SAS AF: 0.312

Gnomad FIN AF: 0.319

Gnomad MID AF: 0.161

Gnomad NFE AF: 0.255

Gnomad OTH AF: 0.207

GnomAD2 exomes AF: 0.244 AC: 61143 AN: 251024 AF XY: 0.252

Gnomad AFR exome AF: 0.0673

Gnomad AMR exome AF: 0.192

Gnomad ASJ exome AF: 0.220

Gnomad EAS exome AF: 0.191

Gnomad FIN exome AF: 0.327

Gnomad NFE exome AF: 0.261

Gnomad OTH exome AF: 0.247

GnomAD4 exome AF: 0.257 AC: 375103 AN: 1461532 Hom.: 49694 Cov.: 37 AF XY: 0.259 AC XY: 188539 AN XY: 727068

African (AFR) AF: 0.0612 AC: 2049 AN: 33466

American (AMR) AF: 0.194 AC: 8670 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.218 AC: 5691 AN: 26126

East Asian (EAS) AF: 0.208 AC: 8236 AN: 39668

South Asian (SAS) AF: 0.307 AC: 26455 AN: 86246

European-Finnish (FIN) AF: 0.320 AC: 17116 AN: 53412

Middle Eastern (MID) AF: 0.204 AC: 1177 AN: 5764

European-Non Finnish (NFE) AF: 0.262 AC: 291010 AN: 1111752

Other (OTH) AF: 0.243 AC: 14699 AN: 60382

GnomAD4 genome AF: 0.201 AC: 30597 AN: 152166 Hom.: 3650 Cov.: 33 AF XY: 0.207 AC XY: 15372 AN XY: 74358

African (AFR) AF: 0.0683 AC: 2838 AN: 41562

American (AMR) AF: 0.201 AC: 3074 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.223 AC: 772 AN: 3466

East Asian (EAS) AF: 0.187 AC: 966 AN: 5168

South Asian (SAS) AF: 0.311 AC: 1497 AN: 4820

European-Finnish (FIN) AF: 0.319 AC: 3377 AN: 10570

Middle Eastern (MID) AF: 0.163 AC: 48 AN: 294

European-Non Finnish (NFE) AF: 0.255 AC: 17338 AN: 67972

Other (OTH) AF: 0.205 AC: 433 AN: 2110

Alfa AF: 0.234 Hom.: 8652

Bravo AF: 0.185

Asia WGS AF: 0.232 AC: 806 AN: 3478

EpiCase AF: 0.247

EpiControl AF: 0.250

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.28
CADD	Benign	1.3
DANN	Benign	0.82
PhyloP100		-1.2
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs3743281; hg19: chr15-48056958; COSMIC: COSV60373705; COSMIC: COSV60373705;