9-89378760-G-C

Variant names:

• chr9-89378760-G-C
• NM_001371194.2:c.2533C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001371194.2(SEMA4D):​c.2533C>G​(p.Pro845Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SEMA4D NM_001371194.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.01
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2983411).

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.2533C>G	p.Pro845Ala	missense	Exon 16 of 16	NP_001358123.1	Q92854-1
	SEMA4D	NM_001371195.1		c.2533C>G	p.Pro845Ala	missense	Exon 17 of 17	NP_001358124.1	Q92854-1
	SEMA4D	NM_001371196.1		c.2533C>G	p.Pro845Ala	missense	Exon 18 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.2533C>G	p.Pro845Ala	missense	Exon 16 of 16	ENSP00000388768.2	Q92854-1
	SEMA4D	ENST00000438547.6	TSL:1	c.2533C>G	p.Pro845Ala	missense	Exon 18 of 18	ENSP00000405102.2	Q92854-1
	SEMA4D	ENST00000450295.5	TSL:1	c.2533C>G	p.Pro845Ala	missense	Exon 16 of 16	ENSP00000416523.1	Q92854-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.032	T
BayesDel_noAF	Benign	-0.28
CADD	Uncertain	26
DANN	Uncertain	0.98
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.0058
Eigen_PC	Benign	-0.058
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.30	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.97	L
PhyloP100		9.0
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.29
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.91	P
Vest4		0.46
MutPred		0.28		Loss of stability (P = 0.0332)
MVP		0.28
MPC		0.86
ClinPred		0.96	D
GERP RS		4.2
Varity_R		0.16
gMVP		0.15
Mutation Taster		=65/35	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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

hg19: chr9-91993675;