15-47770879-T-C

Variant names:

• chr15-47770879-T-C
• rs568215
• NM_001358351.3:c.2316T>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_001358351.3(SEMA6D):​c.2316T>C​(p.Pro772Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.651 in 1,613,666 control chromosomes in the GnomAD database, including 347,312 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 0.73 (42152 hom., cov: 31)
  • Exomes 𝑓: 0.64 (305160 hom.)
• Consequence: SEMA6D NM_001358351.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.752
• Publications: 21 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP7: Synonymous conserved (PhyloP=-0.752 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.92 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SEMA6D	NM_001358351.3	c.2316T>C	p.Pro772Pro	synonymous_variant	Exon 19 of 19	ENST00000536845.7	NP_001345280.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SEMA6D	ENST00000536845.7	c.2316T>C	p.Pro772Pro	synonymous_variant	Exon 19 of 19	2	NM_001358351.3	ENSP00000446152.3

Frequencies

GnomAD3 genomes AF: 0.732 AC: 111066 AN: 151828 Hom.: 42077 Cov.: 31

Gnomad AFR AF: 0.928

Gnomad AMI AF: 0.523

Gnomad AMR AF: 0.683

Gnomad ASJ AF: 0.645

Gnomad EAS AF: 0.832

Gnomad SAS AF: 0.728

Gnomad FIN AF: 0.752

Gnomad MID AF: 0.592

Gnomad NFE AF: 0.621

Gnomad OTH AF: 0.702

GnomAD2 exomes AF: 0.694 AC: 173101 AN: 249470 AF XY: 0.687

Gnomad AFR exome AF: 0.937

Gnomad AMR exome AF: 0.712

Gnomad ASJ exome AF: 0.643

Gnomad EAS exome AF: 0.836

Gnomad FIN exome AF: 0.745

Gnomad NFE exome AF: 0.620

Gnomad OTH exome AF: 0.667

GnomAD4 exome AF: 0.642 AC: 938517 AN: 1461720 Hom.: 305160 Cov.: 72 AF XY: 0.644 AC XY: 468422 AN XY: 727148

African (AFR) AF: 0.940 AC: 31458 AN: 33474

American (AMR) AF: 0.710 AC: 31749 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.640 AC: 16730 AN: 26132

East Asian (EAS) AF: 0.838 AC: 33211 AN: 39654

South Asian (SAS) AF: 0.712 AC: 61428 AN: 86258

European-Finnish (FIN) AF: 0.741 AC: 39571 AN: 53402

Middle Eastern (MID) AF: 0.610 AC: 3515 AN: 5762

European-Non Finnish (NFE) AF: 0.612 AC: 680655 AN: 1111936

Other (OTH) AF: 0.666 AC: 40200 AN: 60396

GnomAD4 genome AF: 0.732 AC: 111201 AN: 151946 Hom.: 42152 Cov.: 31 AF XY: 0.740 AC XY: 54923 AN XY: 74254

African (AFR) AF: 0.928 AC: 38482 AN: 41466

American (AMR) AF: 0.684 AC: 10444 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.645 AC: 2234 AN: 3466

East Asian (EAS) AF: 0.831 AC: 4275 AN: 5142

South Asian (SAS) AF: 0.727 AC: 3497 AN: 4812

European-Finnish (FIN) AF: 0.752 AC: 7941 AN: 10560

Middle Eastern (MID) AF: 0.592 AC: 173 AN: 292

European-Non Finnish (NFE) AF: 0.621 AC: 42187 AN: 67918

Other (OTH) AF: 0.708 AC: 1492 AN: 2108

Alfa AF: 0.647 Hom.: 67596

Bravo AF: 0.734

Asia WGS AF: 0.804 AC: 2796 AN: 3478

EpiCase AF: 0.614

EpiControl AF: 0.609

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	6.7
DANN	Benign	0.52
PhyloP100		-0.75
Mutation Taster		=98/2	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: rs568215; hg19: chr15-48063076; COSMIC: COSV108144111; COSMIC: COSV108144111;