chr9-89388673-C-T

Variant names:

• chr9-89388673-C-T
• rs534671276
• NM_001371194.2:c.1070G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_001371194.2(SEMA4D):​c.1070G>A​(p.Arg357His) variant causes a missense change. The variant allele was found at a frequency of 0.0000312 in 1,604,316 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000032 (0 hom.)
• Consequence: SEMA4D NM_001371194.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.65
• Publications: 1 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001371194.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SEMA4D	NM_001371194.2	MANE Select	c.1070G>A	p.Arg357His	missense	Exon 11 of 16	NP_001358123.1	Q92854-1
	SEMA4D	NM_001371195.1		c.1070G>A	p.Arg357His	missense	Exon 12 of 17	NP_001358124.1	Q92854-1
	SEMA4D	NM_001371196.1		c.1070G>A	p.Arg357His	missense	Exon 13 of 18	NP_001358125.1	Q92854-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SEMA4D	ENST00000422704.7	TSL:1 MANE Select	c.1070G>A	p.Arg357His	missense	Exon 11 of 16	ENSP00000388768.2	Q92854-1
	SEMA4D	ENST00000438547.6	TSL:1	c.1070G>A	p.Arg357His	missense	Exon 13 of 18	ENSP00000405102.2	Q92854-1
	SEMA4D	ENST00000450295.5	TSL:1	c.1070G>A	p.Arg357His	missense	Exon 11 of 16	ENSP00000416523.1	Q92854-1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152224 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000373 AC: 9 AN: 241040 AF XY: 0.0000381

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000308

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000336

Gnomad FIN exome AF: 0.0000558

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000317 AC: 46 AN: 1451974 Hom.: 0 Cov.: 30 AF XY: 0.0000304 AC XY: 22 AN XY: 722586

African (AFR) AF: 0.00 AC: 0 AN: 33154

American (AMR) AF: 0.0000234 AC: 1 AN: 42820

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25802

East Asian (EAS) AF: 0.000958 AC: 38 AN: 39650

South Asian (SAS) AF: 0.0000234 AC: 2 AN: 85596

European-Finnish (FIN) AF: 0.0000205 AC: 1 AN: 48784

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5740

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1110328

Other (OTH) AF: 0.00 AC: 0 AN: 60100

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152342 Hom.: 0 Cov.: 34 AF XY: 0.0000403 AC XY: 3 AN XY: 74488

African (AFR) AF: 0.0000240 AC: 1 AN: 41582

American (AMR) AF: 0.00 AC: 0 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5176

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000412 AC: 5

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Anti-SEMA4D Monoclonal Antibody VX15/2503 (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.34
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.41	T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.029	D
MetaRNN	Uncertain	0.43	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	2.9	M
PhyloP100		3.6
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-3.2	D
REVEL	Benign	0.18
Sift	Uncertain	0.017	D
Sift4G	Uncertain	0.025	D
Polyphen		0.89	P
Vest4		0.62
MutPred		0.58		Loss of MoRF binding (P = 0.0062)
MVP		0.50
MPC		0.48
ClinPred		0.51	D
GERP RS		4.7
Varity_R		0.74
gMVP		0.57
Mutation Taster		=26/74	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs534671276; hg19: chr9-92003588;