15-47348590-T-C

Variant names:

• chr15-47348590-T-C
• rs578458
• ENST00000558014.5:c.-238-63803T>C

Variant summary

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

The NM_001198999.2(SEMA6D):​c.-238-63803T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.468 in 151,368 control chromosomes in the GnomAD database, including 19,674 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 0.47 (19674 hom., cov: 28)
• Consequence: SEMA6D NM_001198999.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.50
• Publications: 3 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=-0.96).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.599 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001198999.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SEMA6D	NM_001198999.2		c.-238-63803T>C		intron	N/A	NP_001185928.1	Q8NFY4-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SEMA6D	ENST00000558014.5	TSL:1	c.-238-63803T>C		intron	N/A	ENSP00000452815.1	Q8NFY4-2
	SEMA6D	ENST00000559184.5	TSL:4	c.-238-63803T>C		intron	N/A	ENSP00000453097.1	H0YL82
	SEMA6D	ENST00000560636.5	TSL:4	c.-323+9371T>C		intron	N/A	ENSP00000453420.1

Frequencies

GnomAD3 genomes AF: 0.469 AC: 70861 AN: 151250 Hom.: 19691 Cov.: 28

Gnomad AFR AF: 0.151

Gnomad AMI AF: 0.515

Gnomad AMR AF: 0.517

Gnomad ASJ AF: 0.574

Gnomad EAS AF: 0.447

Gnomad SAS AF: 0.611

Gnomad FIN AF: 0.672

Gnomad MID AF: 0.449

Gnomad NFE AF: 0.604

Gnomad OTH AF: 0.497

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

GnomAD4 genome AF: 0.468 AC: 70837 AN: 151368 Hom.: 19674 Cov.: 28 AF XY: 0.476 AC XY: 35190 AN XY: 73934

African (AFR) AF: 0.151 AC: 6216 AN: 41240

American (AMR) AF: 0.516 AC: 7824 AN: 15154

Ashkenazi Jewish (ASJ) AF: 0.574 AC: 1989 AN: 3464

East Asian (EAS) AF: 0.447 AC: 2283 AN: 5108

South Asian (SAS) AF: 0.611 AC: 2928 AN: 4794

European-Finnish (FIN) AF: 0.672 AC: 7008 AN: 10432

Middle Eastern (MID) AF: 0.425 AC: 125 AN: 294

European-Non Finnish (NFE) AF: 0.604 AC: 40966 AN: 67872

Other (OTH) AF: 0.490 AC: 1030 AN: 2102

Alfa AF: 0.523 Hom.: 4010

Bravo AF: 0.440

Asia WGS AF: 0.452 AC: 1572 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	1.0
DANN	Benign	0.76
PhyloP100		-1.5
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: rs578458; hg19: chr15-47640787;