9-89363868-G-A

Position:

• chr9-89363868-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BA1

The NM_001142287.2(SEMA4D):​c.1965C>T​(p.Pro655Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.143 in 1,614,018 control chromosomes in the GnomAD database, including 20,110 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.12 (1777 hom., cov: 33)
  • Exomes 𝑓: 0.14 (18333 hom.)
• Consequence: SEMA4D NM_001142287.2 synonymous
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -1.50

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]

SEMA4D (HGNC:):

SECISBP2 (HGNC:30972): (SECIS binding protein 2) The protein encoded by this gene is one of the essential components of the machinery involved in co-translational insertion of selenocysteine (Sec) into selenoproteins. Sec is encoded by the UGA codon, which normally signals translation termination. The recoding of UGA as Sec codon requires a Sec insertion sequence (SECIS) element; present in the 3' untranslated regions of eukaryotic selenoprotein mRNAs. This protein specifically binds to the SECIS element, which is stimulated by a Sec-specific translation elongation factor. Mutations in this gene have been associated with reduction in enzymatic activity of type II iodothyronine deiodinase (a selenoprotein) and abnormal thyroid hormone metabolism. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Aug 2017]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 9-89363868-G-A is Benign according to our data. Variant chr9-89363868-G-A is described in ClinVar as [Benign]. Clinvar id is 3060340.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=-1.5 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.286 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SEMA4D	XM_047422629.1	c.1529C>T	p.Pro510Leu	missense_variant	18/18		XP_047278585.1
SEMA4D	NM_001142287.2	c.1965C>T	p.Pro655Pro	synonymous_variant	19/21		NP_001135759.1
SEMA4D	NM_001371198.1	c.1965C>T	p.Pro655Pro	synonymous_variant	17/19		NP_001358127.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SEMA4D	ENST00000420101.6	c.120C>T	p.Pro40Pro	synonymous_variant	1/3	1		ENSP00000399948.2
SEMA4D	ENST00000475255.5	n.1787C>T		non_coding_transcript_exon_variant	1/2	1
SEMA4D	ENST00000339861.8	c.1965C>T	p.Pro655Pro	synonymous_variant	17/19	5		ENSP00000344923.4

Frequencies

GnomAD3 genomes AF: 0.124 AC: 18808 AN: 152144 Hom.: 1769 Cov.: 33

Gnomad AFR AF: 0.0311

Gnomad AMI AF: 0.155

Gnomad AMR AF: 0.293

Gnomad ASJ AF: 0.0888

Gnomad EAS AF: 0.203

Gnomad SAS AF: 0.135

Gnomad FIN AF: 0.141

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.135

Gnomad OTH AF: 0.111

GnomAD3 exomes AF: 0.176 AC: 44288 AN: 251246 Hom.: 5991 AF XY: 0.166 AC XY: 22504 AN XY: 135828

Gnomad AFR exome AF: 0.0289

Gnomad AMR exome AF: 0.453

Gnomad ASJ exome AF: 0.0823

Gnomad EAS exome AF: 0.209

Gnomad SAS exome AF: 0.137

Gnomad FIN exome AF: 0.152

Gnomad NFE exome AF: 0.133

Gnomad OTH exome AF: 0.139

GnomAD4 exome AF: 0.145 AC: 211597 AN: 1461756 Hom.: 18333 Cov.: 33 AF XY: 0.143 AC XY: 103814 AN XY: 727166

Gnomad4 AFR exome AF: 0.0234

Gnomad4 AMR exome AF: 0.434

Gnomad4 ASJ exome AF: 0.0832

Gnomad4 EAS exome AF: 0.158

Gnomad4 SAS exome AF: 0.135

Gnomad4 FIN exome AF: 0.159

Gnomad4 NFE exome AF: 0.139

Gnomad4 OTH exome AF: 0.130

GnomAD4 genome AF: 0.124 AC: 18828 AN: 152262 Hom.: 1777 Cov.: 33 AF XY: 0.127 AC XY: 9488 AN XY: 74434

Gnomad4 AFR AF: 0.0310

Gnomad4 AMR AF: 0.294

Gnomad4 ASJ AF: 0.0888

Gnomad4 EAS AF: 0.203

Gnomad4 SAS AF: 0.135

Gnomad4 FIN AF: 0.141

Gnomad4 NFE AF: 0.135

Gnomad4 OTH AF: 0.112

Alfa AF: 0.0962 Hom.: 345

Bravo AF: 0.133

Asia WGS AF: 0.192 AC: 665 AN: 3478

EpiCase AF: 0.119

EpiControl AF: 0.121

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

SEMA4D-related disorder Benign:1

Benign, no assertion criteria provided

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_noAF	Benign	-0.81
CADD	Benign	0.075
DANN	Benign	0.68

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs45515192; hg19: chr9-91978783; COSMIC: COSV59392394; COSMIC: COSV59392394;