rs688475

Variant names:

• chr15-47739270-G-A
• rs688475
• NM_001358351.3:c.-54-20475G>A

Variant summary

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

The NM_001358351.3(SEMA6D):​c.-54-20475G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.29 in 152,064 control chromosomes in the GnomAD database, including 7,895 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 0.29 (7895 hom., cov: 32)
• Consequence: SEMA6D NM_001358351.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.400
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.392 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SEMA6D	NM_001358351.3	c.-54-20475G>A		intron_variant	Intron 1 of 18	ENST00000536845.7	NP_001345280.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SEMA6D	ENST00000536845.7	c.-54-20475G>A		intron_variant	Intron 1 of 18	2	NM_001358351.3	ENSP00000446152.3

Frequencies

GnomAD3 genomes AF: 0.290 AC: 44098 AN: 151946 Hom.: 7895 Cov.: 32

Gnomad AFR AF: 0.0774

Gnomad AMI AF: 0.478

Gnomad AMR AF: 0.352

Gnomad ASJ AF: 0.371

Gnomad EAS AF: 0.279

Gnomad SAS AF: 0.284

Gnomad FIN AF: 0.312

Gnomad MID AF: 0.396

Gnomad NFE AF: 0.396

Gnomad OTH AF: 0.318

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

GnomAD4 genome AF: 0.290 AC: 44093 AN: 152064 Hom.: 7895 Cov.: 32 AF XY: 0.286 AC XY: 21221 AN XY: 74316

African (AFR) AF: 0.0772 AC: 3205 AN: 41534

American (AMR) AF: 0.352 AC: 5377 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.371 AC: 1287 AN: 3470

East Asian (EAS) AF: 0.279 AC: 1442 AN: 5160

South Asian (SAS) AF: 0.286 AC: 1376 AN: 4814

European-Finnish (FIN) AF: 0.312 AC: 3297 AN: 10574

Middle Eastern (MID) AF: 0.398 AC: 117 AN: 294

European-Non Finnish (NFE) AF: 0.396 AC: 26896 AN: 67920

Other (OTH) AF: 0.313 AC: 661 AN: 2110

Alfa AF: 0.317 Hom.: 1139

Bravo AF: 0.287

Asia WGS AF: 0.246 AC: 856 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.41
DANN	Benign	0.55
PhyloP100		-0.40
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs688475; hg19: chr15-48031467;