rs1559677

Variant names:

• chr15-47445866-A-G
• rs1559677
• ENST00000558014.5:c.-158-24608A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000558014.5(SEMA6D):​c.-158-24608A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.496 in 151,824 control chromosomes in the GnomAD database, including 20,514 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 0.50 (20514 hom., cov: 31)
• Consequence: SEMA6D ENST00000558014.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0340
• Publications: 13 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.733 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SEMA6D	NM_001198999.2	c.-158-24608A>G		intron_variant	Intron 2 of 19		NP_001185928.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SEMA6D	ENST00000558014.5	c.-158-24608A>G		intron_variant	Intron 2 of 19	1		ENSP00000452815.1
SEMA6D	ENST00000559184.5	c.-158-24608A>G		intron_variant	Intron 3 of 5	4		ENSP00000453097.1
SEMA6D	ENST00000560636.5	c.-242-24608A>G		intron_variant	Intron 2 of 5	4		ENSP00000453420.1

Frequencies

GnomAD3 genomes AF: 0.496 AC: 75186 AN: 151706 Hom.: 20481 Cov.: 31

Gnomad AFR AF: 0.739

Gnomad AMI AF: 0.499

Gnomad AMR AF: 0.431

Gnomad ASJ AF: 0.390

Gnomad EAS AF: 0.459

Gnomad SAS AF: 0.540

Gnomad FIN AF: 0.422

Gnomad MID AF: 0.294

Gnomad NFE AF: 0.380

Gnomad OTH AF: 0.472

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.496 AC: 75272 AN: 151824 Hom.: 20514 Cov.: 31 AF XY: 0.497 AC XY: 36836 AN XY: 74158

African (AFR) AF: 0.740 AC: 30623 AN: 41406

American (AMR) AF: 0.431 AC: 6570 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.390 AC: 1354 AN: 3470

East Asian (EAS) AF: 0.458 AC: 2336 AN: 5098

South Asian (SAS) AF: 0.539 AC: 2590 AN: 4806

European-Finnish (FIN) AF: 0.422 AC: 4446 AN: 10542

Middle Eastern (MID) AF: 0.286 AC: 84 AN: 294

European-Non Finnish (NFE) AF: 0.380 AC: 25824 AN: 67944

Other (OTH) AF: 0.470 AC: 993 AN: 2112

Alfa AF: 0.417 Hom.: 60772

Bravo AF: 0.507

Asia WGS AF: 0.533 AC: 1854 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	5.1
DANN	Benign	0.66
PhyloP100		0.034
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs1559677; hg19: chr15-47738063;