rs1224662

Variant names:

• chr15-47710350-T-A
• rs1224662
• ENST00000558014.5:c.-54-49395T>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The ENST00000558014.5(SEMA6D):​c.-54-49395T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.916 in 152,230 control chromosomes in the GnomAD database, including 64,509 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 0.92 (64509 hom., cov: 32)
• Consequence: SEMA6D ENST00000558014.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.37
• Publications: 0 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.944 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SEMA6D	NM_001198999.2	c.-54-49395T>A		intron_variant	Intron 4 of 19		NP_001185928.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SEMA6D	ENST00000558014.5	c.-54-49395T>A		intron_variant	Intron 4 of 19	1		ENSP00000452815.1
SEMA6D	ENST00000559184.5	c.-54-49395T>A		intron_variant	Intron 5 of 5	4		ENSP00000453097.1
SEMA6D	ENST00000560636.5	c.-54-49395T>A		intron_variant	Intron 5 of 5	4		ENSP00000453420.1

Frequencies

GnomAD3 genomes AF: 0.916 AC: 139389 AN: 152112 Hom.: 64464 Cov.: 32

Gnomad AFR AF: 0.934

Gnomad AMI AF: 0.904

Gnomad AMR AF: 0.862

Gnomad ASJ AF: 0.960

Gnomad EAS AF: 0.492

Gnomad SAS AF: 0.829

Gnomad FIN AF: 0.942

Gnomad MID AF: 0.940

Gnomad NFE AF: 0.950

Gnomad OTH AF: 0.909

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

GnomAD4 genome AF: 0.916 AC: 139493 AN: 152230 Hom.: 64509 Cov.: 32 AF XY: 0.911 AC XY: 67786 AN XY: 74416

African (AFR) AF: 0.934 AC: 38814 AN: 41542

American (AMR) AF: 0.861 AC: 13162 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.960 AC: 3334 AN: 3472

East Asian (EAS) AF: 0.493 AC: 2551 AN: 5170

South Asian (SAS) AF: 0.829 AC: 4000 AN: 4826

European-Finnish (FIN) AF: 0.942 AC: 9969 AN: 10580

Middle Eastern (MID) AF: 0.939 AC: 276 AN: 294

European-Non Finnish (NFE) AF: 0.950 AC: 64653 AN: 68038

Other (OTH) AF: 0.905 AC: 1910 AN: 2110

Alfa AF: 0.937 Hom.: 8323

Bravo AF: 0.907

Asia WGS AF: 0.664 AC: 2307 AN: 3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
CADD	Benign	18
DANN	Benign	0.80
PhyloP100		1.4
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: rs1224662; hg19: chr15-48002547;