chr15-47765874-G-A

Variant names:

• chr15-47765874-G-A
• rs532598
• NM_001358351.3:c.1433G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_001358352.2(SEMA6D):​c.1433G>A​(p.Ser478Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.36 in 1,510,420 control chromosomes in the GnomAD database, including 102,674 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S478T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.43 (15188 hom., cov: 33)
  • Exomes 𝑓: 0.35 (87486 hom.)
• Consequence: SEMA6D NM_001358352.2 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.310
• Publications: 36 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=8.88815E-6).
• BP6: Variant 15-47765874-G-A is Benign according to our data. Variant chr15-47765874-G-A is described in ClinVar as Benign. ClinVar VariationId is 3060165.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.575 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001358352.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SEMA6D	NM_001358351.3	MANE Select	c.1433G>A	p.Ser478Asn	missense	Exon 14 of 19	NP_001345280.1
	SEMA6D	NM_001358352.2		c.1433G>A	p.Ser478Asn	missense	Exon 14 of 19	NP_001345281.1
	SEMA6D	NM_153618.2		c.1433G>A	p.Ser478Asn	missense	Exon 14 of 19	NP_705871.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SEMA6D	ENST00000536845.7	TSL:2 MANE Select	c.1433G>A	p.Ser478Asn	missense	Exon 14 of 19	ENSP00000446152.3
	SEMA6D	ENST00000316364.9	TSL:1	c.1433G>A	p.Ser478Asn	missense	Exon 14 of 19	ENSP00000324857.5
	SEMA6D	ENST00000354744.8	TSL:1	c.1433G>A	p.Ser478Asn	missense	Exon 14 of 18	ENSP00000346786.4

Frequencies

GnomAD3 genomes AF: 0.433 AC: 65833 AN: 151910 Hom.: 15183 Cov.: 33

Gnomad AFR AF: 0.582

Gnomad AMI AF: 0.218

Gnomad AMR AF: 0.413

Gnomad ASJ AF: 0.386

Gnomad EAS AF: 0.591

Gnomad SAS AF: 0.349

Gnomad FIN AF: 0.443

Gnomad MID AF: 0.342

Gnomad NFE AF: 0.346

Gnomad OTH AF: 0.414

GnomAD2 exomes AF: 0.398 AC: 72000 AN: 180842 AF XY: 0.389

Gnomad AFR exome AF: 0.584

Gnomad AMR exome AF: 0.396

Gnomad ASJ exome AF: 0.390

Gnomad EAS exome AF: 0.588

Gnomad FIN exome AF: 0.433

Gnomad NFE exome AF: 0.336

Gnomad OTH exome AF: 0.385

GnomAD4 exome AF: 0.352 AC: 478237 AN: 1358392 Hom.: 87486 Cov.: 34 AF XY: 0.352 AC XY: 233888 AN XY: 664896

African (AFR) AF: 0.591 AC: 17797 AN: 30106

American (AMR) AF: 0.404 AC: 12116 AN: 29970

Ashkenazi Jewish (ASJ) AF: 0.384 AC: 7675 AN: 20010

East Asian (EAS) AF: 0.596 AC: 23003 AN: 38590

South Asian (SAS) AF: 0.341 AC: 22985 AN: 67356

European-Finnish (FIN) AF: 0.431 AC: 21426 AN: 49674

Middle Eastern (MID) AF: 0.349 AC: 1844 AN: 5282

European-Non Finnish (NFE) AF: 0.330 AC: 350486 AN: 1061502

Other (OTH) AF: 0.374 AC: 20905 AN: 55902

GnomAD4 genome AF: 0.433 AC: 65879 AN: 152028 Hom.: 15188 Cov.: 33 AF XY: 0.438 AC XY: 32539 AN XY: 74284

African (AFR) AF: 0.581 AC: 24099 AN: 41476

American (AMR) AF: 0.413 AC: 6311 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.386 AC: 1338 AN: 3464

East Asian (EAS) AF: 0.591 AC: 3048 AN: 5160

South Asian (SAS) AF: 0.350 AC: 1685 AN: 4812

European-Finnish (FIN) AF: 0.443 AC: 4682 AN: 10558

Middle Eastern (MID) AF: 0.337 AC: 99 AN: 294

European-Non Finnish (NFE) AF: 0.346 AC: 23540 AN: 67958

Other (OTH) AF: 0.415 AC: 879 AN: 2116

Alfa AF: 0.374 Hom.: 41035

Bravo AF: 0.436

TwinsUK AF: 0.333 AC: 1233

ALSPAC AF: 0.342 AC: 1317

ESP6500AA AF: 0.587 AC: 2581

ESP6500EA AF: 0.334 AC: 2874

ExAC AF: 0.384 AC: 45777

Asia WGS AF: 0.468 AC: 1626 AN: 3476

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	SEMA6D-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.82	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	1.6
DANN	Benign	0.68
DEOGEN2	Benign	0.041	T
Eigen	Benign	-0.99
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.31	T
MetaRNN	Benign	0.0000089	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.92	L
PhyloP100		0.31
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.89	N
REVEL	Benign	0.032
Sift	Benign	0.39	T
Sift4G	Benign	0.98	T
Polyphen		0.0	B
Vest4		0.050
MPC		0.072
ClinPred		0.0010	T
GERP RS		-1.9
Varity_R		0.052
gMVP		0.13
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: rs532598; hg19: chr15-48058071; COSMIC: COSV105881756; COSMIC: COSV105881756;