9-89363482-C-T

Position:

• chr9-89363482-C-T

Variant summary

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

The ENST00000420101.6(SEMA4D):​c.293G>A​(p.Arg98Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.144 in 1,613,984 control chromosomes in the GnomAD database, including 20,257 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/13 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.13 (1809 hom., cov: 33)
  • Exomes 𝑓: 0.15 (18448 hom.)
• Consequence: SEMA4D ENST00000420101.6 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.280

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]

SECISBP2 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=9.0554357E-4).
• BP6: Variant 9-89363482-C-T is Benign according to our data. Variant chr9-89363482-C-T is described in ClinVar as [Benign]. Clinvar id is 3060820.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.288 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SEMA4D	NM_001142287.2	c.2138G>A	p.Arg713Lys	missense_variant	20/21
SEMA4D	NM_001371198.1	c.2138G>A	p.Arg713Lys	missense_variant	18/19
SEMA4D	NM_001371199.1	c.2138G>A	p.Arg713Lys	missense_variant	19/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SEMA4D	ENST00000420101.6	c.293G>A	p.Arg98Lys	missense_variant	2/3	1
SEMA4D	ENST00000475255.5	n.2173G>A		non_coding_transcript_exon_variant	1/2	1
SEMA4D	ENST00000339861.8	c.2138G>A	p.Arg713Lys	missense_variant	18/19	5

Frequencies

GnomAD3 genomes AF: 0.127 AC: 19385 AN: 152144 Hom.: 1801 Cov.: 33

Gnomad AFR AF: 0.0433

Gnomad AMI AF: 0.155

Gnomad AMR AF: 0.294

Gnomad ASJ AF: 0.0888

Gnomad EAS AF: 0.203

Gnomad SAS AF: 0.136

Gnomad FIN AF: 0.141

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.135

Gnomad OTH AF: 0.112

GnomAD3 exomes AF: 0.178 AC: 44590 AN: 251200 Hom.: 6020 AF XY: 0.167 AC XY: 22654 AN XY: 135782

Gnomad AFR exome AF: 0.0407

Gnomad AMR exome AF: 0.453

Gnomad ASJ exome AF: 0.0820

Gnomad EAS exome AF: 0.209

Gnomad SAS exome AF: 0.139

Gnomad FIN exome AF: 0.153

Gnomad NFE exome AF: 0.134

Gnomad OTH exome AF: 0.139

GnomAD4 exome AF: 0.145 AC: 212484 AN: 1461722 Hom.: 18448 Cov.: 33 AF XY: 0.143 AC XY: 104305 AN XY: 727170

Gnomad4 AFR exome AF: 0.0364

Gnomad4 AMR exome AF: 0.435

Gnomad4 ASJ exome AF: 0.0832

Gnomad4 EAS exome AF: 0.159

Gnomad4 SAS exome AF: 0.137

Gnomad4 FIN exome AF: 0.159

Gnomad4 NFE exome AF: 0.139

Gnomad4 OTH exome AF: 0.131

GnomAD4 genome AF: 0.127 AC: 19410 AN: 152262 Hom.: 1809 Cov.: 33 AF XY: 0.131 AC XY: 9771 AN XY: 74448

Gnomad4 AFR AF: 0.0433

Gnomad4 AMR AF: 0.295

Gnomad4 ASJ AF: 0.0888

Gnomad4 EAS AF: 0.203

Gnomad4 SAS AF: 0.136

Gnomad4 FIN AF: 0.141

Gnomad4 NFE AF: 0.135

Gnomad4 OTH AF: 0.114

Alfa AF: 0.125 Hom.: 1384

Bravo AF: 0.136

TwinsUK AF: 0.130 AC: 482

ALSPAC AF: 0.141 AC: 544

ESP6500AA AF: 0.0418 AC: 184

ESP6500EA AF: 0.133 AC: 1147

ExAC AF: 0.163 AC: 19730

Asia WGS AF: 0.193 AC: 670 AN: 3478

EpiCase AF: 0.120

EpiControl AF: 0.121

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

SEMA4D-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 18, 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
BayesDel_addAF	Benign	-0.78	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	14
DANN	Benign	0.95
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.13	N
MetaRNN	Benign	0.00091	T;T;T;T
MetaSVM	Benign	-0.91	T
MutationTaster	Benign	1.0	P;P;P;P;P
PROVEAN	Benign	-0.090	N;N;N;N
REVEL	Benign	0.026
Sift	Benign	0.47	T;T;T;T
Sift4G	Benign	0.42	T;T;D;T
Polyphen		0.0040	B;B;.;B
Vest4		0.10
ClinPred		0.0021	T
GERP RS		0.79

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs13295305; hg19: chr9-91978397; COSMIC: COSV59394932; COSMIC: COSV59394932;