chr9-89388673-C-A

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001371194.2(SEMA4D):​c.1070G>T​(p.Arg357Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000207 in 1,451,974 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R357H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SEMA4D NM_001371194.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.65
• Publications: 0 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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>T	p.Arg357Leu	missense	Exon 11 of 16	NP_001358123.1	Q92854-1
	SEMA4D	NM_001371195.1		c.1070G>T	p.Arg357Leu	missense	Exon 12 of 17	NP_001358124.1	Q92854-1
	SEMA4D	NM_001371196.1		c.1070G>T	p.Arg357Leu	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>T	p.Arg357Leu	missense	Exon 11 of 16	ENSP00000388768.2	Q92854-1
	SEMA4D	ENST00000438547.6	TSL:1	c.1070G>T	p.Arg357Leu	missense	Exon 13 of 18	ENSP00000405102.2	Q92854-1
	SEMA4D	ENST00000450295.5	TSL:1	c.1070G>T	p.Arg357Leu	missense	Exon 11 of 16	ENSP00000416523.1	Q92854-1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000207 AC: 3 AN: 1451974 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 722586

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

American (AMR) AF: 0.00 AC: 0 AN: 42820

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39650

South Asian (SAS) AF: 0.00 AC: 0 AN: 85596

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48784

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

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1110328

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

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Benign	-0.030	T
BayesDel_noAF	Benign	-0.28
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T
Eigen	Benign	0.066
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.025	D
MetaRNN	Uncertain	0.58	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		3.6
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-3.5	D
REVEL	Benign	0.12
Sift	Uncertain	0.026	D
Sift4G	Benign	0.062	T
Polyphen		0.0080	B
Vest4		0.76
MutPred		0.64		Loss of MoRF binding (P = 0.0034)
MVP		0.40
MPC		0.40
ClinPred		0.98	D
GERP RS		4.7
Varity_R		0.81
gMVP		0.73
Mutation Taster		=17/83	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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;