rs4775692

Variant names:

• chr15-47519858-C-A
• rs4775692
• ENST00000558014.5:c.-87+49313C>A

Variant summary

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

The ENST00000558014.5(SEMA6D):​c.-87+49313C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0922 in 152,220 control chromosomes in the GnomAD database, including 940 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 0.092 (940 hom., cov: 33)
• Consequence: SEMA6D ENST00000558014.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.279
• 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=-0.69).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.311 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SEMA6D	NM_001198999.2	c.-87+49313C>A		intron_variant	Intron 3 of 19		NP_001185928.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SEMA6D	ENST00000558014.5	c.-87+49313C>A		intron_variant	Intron 3 of 19	1		ENSP00000452815.1
SEMA6D	ENST00000559184.5	c.-87+49313C>A		intron_variant	Intron 4 of 5	4		ENSP00000453097.1
SEMA6D	ENST00000560636.5	c.-171+49313C>A		intron_variant	Intron 3 of 5	4		ENSP00000453420.1

Frequencies

GnomAD3 genomes AF: 0.0922 AC: 14027 AN: 152100 Hom.: 939 Cov.: 33

Gnomad AFR AF: 0.101

Gnomad AMI AF: 0.104

Gnomad AMR AF: 0.172

Gnomad ASJ AF: 0.0559

Gnomad EAS AF: 0.325

Gnomad SAS AF: 0.0900

Gnomad FIN AF: 0.0344

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0621

Gnomad OTH AF: 0.0956

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

GnomAD4 genome AF: 0.0922 AC: 14040 AN: 152220 Hom.: 940 Cov.: 33 AF XY: 0.0942 AC XY: 7012 AN XY: 74420

African (AFR) AF: 0.101 AC: 4206 AN: 41532

American (AMR) AF: 0.172 AC: 2633 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0559 AC: 194 AN: 3470

East Asian (EAS) AF: 0.324 AC: 1680 AN: 5180

South Asian (SAS) AF: 0.0895 AC: 431 AN: 4818

European-Finnish (FIN) AF: 0.0344 AC: 365 AN: 10600

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0621 AC: 4223 AN: 68010

Other (OTH) AF: 0.0964 AC: 204 AN: 2116

Alfa AF: 0.0717 Hom.: 77

Bravo AF: 0.106

Asia WGS AF: 0.199 AC: 691 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	11
DANN	Benign	0.64
PhyloP100		0.28
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: rs4775692; hg19: chr15-47812055;