chr15-47766572-T-A

Position:

• chr15-47766572-T-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The ENST00000358066.8(SEMA6D):​c.1647-5T>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0315 in 1,600,272 control chromosomes in the GnomAD database, including 1,110 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.024 (88 hom., cov: 32)
  • Exomes 𝑓: 0.032 (1022 hom.)
• Consequence: SEMA6D ENST00000358066.8 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.009559
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.91

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0729 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SEMA6D	NM_001358351.3	c.1647-44T>A		intron_variant		ENST00000536845.7	NP_001345280.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SEMA6D	ENST00000536845.7	c.1647-44T>A		intron_variant		2	NM_001358351.3	ENSP00000446152	P4

Frequencies

GnomAD3 genomes AF: 0.0238 AC: 3618 AN: 152088 Hom.: 89 Cov.: 32

Gnomad AFR AF: 0.00529

Gnomad AMI AF: 0.0515

Gnomad AMR AF: 0.0111

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.0577

Gnomad SAS AF: 0.0805

Gnomad FIN AF: 0.0422

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0293

Gnomad OTH AF: 0.0181

GnomAD3 exomes AF: 0.0332 AC: 8304 AN: 250224 Hom.: 270 AF XY: 0.0354 AC XY: 4788 AN XY: 135274

Gnomad AFR exome AF: 0.00550

Gnomad AMR exome AF: 0.00981

Gnomad ASJ exome AF: 0.00518

Gnomad EAS exome AF: 0.0682

Gnomad SAS exome AF: 0.0747

Gnomad FIN exome AF: 0.0460

Gnomad NFE exome AF: 0.0279

Gnomad OTH exome AF: 0.0251

GnomAD4 exome AF: 0.0324 AC: 46866 AN: 1448066 Hom.: 1022 Cov.: 28 AF XY: 0.0335 AC XY: 24175 AN XY: 721374

Gnomad4 AFR exome AF: 0.00419

Gnomad4 AMR exome AF: 0.0104

Gnomad4 ASJ exome AF: 0.00478

Gnomad4 EAS exome AF: 0.0430

Gnomad4 SAS exome AF: 0.0683

Gnomad4 FIN exome AF: 0.0449

Gnomad4 NFE exome AF: 0.0311

Gnomad4 OTH exome AF: 0.0319

GnomAD4 genome AF: 0.0237 AC: 3613 AN: 152206 Hom.: 88 Cov.: 32 AF XY: 0.0259 AC XY: 1927 AN XY: 74426

Gnomad4 AFR AF: 0.00527

Gnomad4 AMR AF: 0.0111

Gnomad4 ASJ AF: 0.00375

Gnomad4 EAS AF: 0.0578

Gnomad4 SAS AF: 0.0795

Gnomad4 FIN AF: 0.0422

Gnomad4 NFE AF: 0.0293

Gnomad4 OTH AF: 0.0184

Alfa AF: 0.0173 Hom.: 15

Bravo AF: 0.0197

Asia WGS AF: 0.0790 AC: 274 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Pathogenic	31
DANN	Benign	0.88

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0096
dbscSNV1_RF	Benign	0.024
SpliceAI score (max)		0.51		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.51		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs16960071; hg19: chr15-48058769;