rs3985863

Variant names:

• chr15-47741171-G-A
• rs3985863
• NM_001358351.3:c.-54-18574G>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.-54-18574G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0999 in 152,030 control chromosomes in the GnomAD database, including 1,015 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 0.10 (1015 hom., cov: 32)
• Consequence: SEMA6D NM_001358351.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.22
• Publications: 1 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=-0.83).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.139 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SEMA6D	NM_001358351.3	c.-54-18574G>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.-54-18574G>A		intron_variant	Intron 1 of 18	2	NM_001358351.3	ENSP00000446152.3

Frequencies

GnomAD3 genomes AF: 0.100 AC: 15185 AN: 151912 Hom.: 1014 Cov.: 32

Gnomad AFR AF: 0.0250

Gnomad AMI AF: 0.130

Gnomad AMR AF: 0.0789

Gnomad ASJ AF: 0.166

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.147

Gnomad FIN AF: 0.159

Gnomad MID AF: 0.117

Gnomad NFE AF: 0.141

Gnomad OTH AF: 0.0988

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

GnomAD4 genome AF: 0.0999 AC: 15183 AN: 152030 Hom.: 1015 Cov.: 32 AF XY: 0.101 AC XY: 7493 AN XY: 74290

African (AFR) AF: 0.0249 AC: 1032 AN: 41468

American (AMR) AF: 0.0788 AC: 1203 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.166 AC: 576 AN: 3470

East Asian (EAS) AF: 0.00155 AC: 8 AN: 5170

South Asian (SAS) AF: 0.148 AC: 709 AN: 4798

European-Finnish (FIN) AF: 0.159 AC: 1684 AN: 10560

Middle Eastern (MID) AF: 0.112 AC: 33 AN: 294

European-Non Finnish (NFE) AF: 0.141 AC: 9613 AN: 67978

Other (OTH) AF: 0.0982 AC: 207 AN: 2108

Alfa AF: 0.111 Hom.: 633

Bravo AF: 0.0885

Asia WGS AF: 0.0570 AC: 197 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	6.9
DANN	Benign	0.43
PhyloP100		2.2
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: rs3985863; hg19: chr15-48033368;