rs11526468

chr9-89388764-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001371194.2(SEMA4D):c.979G>A(p.Ala327Thr) variant causes a missense change. The variant allele was found at a frequency of 0.282 in 1,607,020 control chromosomes in the GnomAD database, including 66,595 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.23 (4774 hom., cov: 33)
  • Exomes 𝑓: 0.29 (61821 hom.)
• Consequence: SEMA4D NM_001371194.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.76

Genes affected

SEMA4D (HGNC:10732): (semaphorin 4D) Enables identical protein binding activity; semaphorin receptor binding activity; and transmembrane signaling receptor activity. Involved in several processes, including positive regulation of phosphatidylinositol 3-kinase signaling; regulation of neuron projection development; and regulation of phosphate metabolic process. Is integral component of plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002583325).
• BP6: Variant 9-89388764-C-T is Benign according to our data. Variant chr9-89388764-C-T is described in ClinVar as [Benign]. Clinvar id is 3060636.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.323 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SEMA4D	NM_001371194.2	c.979G>A	p.Ala327Thr	missense_variant	11/16	ENST00000422704.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SEMA4D	ENST00000422704.7	c.979G>A	p.Ala327Thr	missense_variant	11/16	1	NM_001371194.2	P1

Frequencies

GnomAD3 genomes AF: 0.226 AC: 34369 AN: 152060 Hom.: 4772 Cov.: 33

Gnomad AFR AF: 0.0561

Gnomad AMI AF: 0.176

Gnomad AMR AF: 0.255

Gnomad ASJ AF: 0.209

Gnomad EAS AF: 0.337

Gnomad SAS AF: 0.266

Gnomad FIN AF: 0.327

Gnomad MID AF: 0.158

Gnomad NFE AF: 0.297

Gnomad OTH AF: 0.255

GnomAD3 exomes AF: 0.273 AC: 67540 AN: 247554 Hom.: 9646 AF XY: 0.277 AC XY: 37131 AN XY: 133940

Gnomad AFR exome AF: 0.0511

Gnomad AMR exome AF: 0.257

Gnomad ASJ exome AF: 0.198

Gnomad EAS exome AF: 0.335

Gnomad SAS exome AF: 0.272

Gnomad FIN exome AF: 0.325

Gnomad NFE exome AF: 0.296

Gnomad OTH exome AF: 0.284

GnomAD4 exome AF: 0.288 AC: 419505 AN: 1454842 Hom.: 61821 Cov.: 39 AF XY: 0.289 AC XY: 208678 AN XY: 722676

Gnomad4 AFR exome AF: 0.0470

Gnomad4 AMR exome AF: 0.262

Gnomad4 ASJ exome AF: 0.198

Gnomad4 EAS exome AF: 0.365

Gnomad4 SAS exome AF: 0.269

Gnomad4 FIN exome AF: 0.318

Gnomad4 NFE exome AF: 0.297

Gnomad4 OTH exome AF: 0.270

GnomAD4 genome AF: 0.226 AC: 34365 AN: 152178 Hom.: 4774 Cov.: 33 AF XY: 0.228 AC XY: 16944 AN XY: 74382

Gnomad4 AFR AF: 0.0560

Gnomad4 AMR AF: 0.254

Gnomad4 ASJ AF: 0.209

Gnomad4 EAS AF: 0.336

Gnomad4 SAS AF: 0.265

Gnomad4 FIN AF: 0.327

Gnomad4 NFE AF: 0.297

Gnomad4 OTH AF: 0.260

Alfa AF: 0.285 Hom.: 9584

Bravo AF: 0.214

TwinsUK AF: 0.285 AC: 1057

ALSPAC AF: 0.287 AC: 1108

ESP6500AA AF: 0.0631 AC: 278

ESP6500EA AF: 0.289 AC: 2486

ExAC AF: 0.270 AC: 32819

Asia WGS AF: 0.272 AC: 945 AN: 3478

EpiCase AF: 0.292

EpiControl AF: 0.300

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

SEMA4D-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 21, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.37
Cadd	Uncertain	24
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.97	D
MetaRNN	Benign	0.0026	T;T;T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.5	M;M;M;M;M;M;M
MutationTaster	Benign	0.0000088	P;P;P;P;P;P;P;P
PrimateAI	Benign	0.48	T
PROVEAN	Uncertain	-2.8	D;D;D;D;D;D;D
REVEL	Benign	0.29
Sift	Benign	0.069	T;T;T;T;T;T;T
Sift4G	Uncertain	0.047	D;D;D;D;D;D;D
Polyphen		1.0	D;D;D;D;D;D;D
Vest4		0.44
MPC		0.69
ClinPred		0.020	T
GERP RS		4.0
Varity_R		0.64
gMVP		0.66

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs11526468; hg19: chr9-92003679; COSMIC: COSV59399979; COSMIC: COSV59399979;