9-70598652-C-T

Position:

• chr9-70598652-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_001366145.2(TRPM3):​c.2815G>A​(p.Gly939Arg) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TRPM3 NM_001366145.2 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 7.89

Genes affected

TRPM3 (HGNC:17992): (transient receptor potential cation channel subfamily M member 3) The product of this gene belongs to the family of transient receptor potential (TRP) channels. TRP channels are cation-selective channels important for cellular calcium signaling and homeostasis. The protein encoded by this gene mediates calcium entry, and this entry is potentiated by calcium store depletion. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), TRPM3. . Gene score misZ 3.1768 (greater than the threshold 3.09). Trascript score misZ 3.8237 (greater than threshold 3.09). GenCC has associacion of gene with intellectual disability, schizophrenia, autosomal dominant non-syndromic intellectual disability, cataract-glaucoma syndrome, neurodevelopmental disorder with hypotonia, dysmorphic facies, and skeletal anomalies, with or without seizures, cataract 50 with or without glaucoma.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.832

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRPM3	NM_001366145.2	c.2815G>A	p.Gly939Arg	missense_variant	21/26	ENST00000677713.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRPM3	ENST00000677713.2	c.2815G>A	p.Gly939Arg	missense_variant	21/26		NM_001366145.2	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Malignant tumor of prostate Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

Science for Life laboratory, Karolinska Institutet

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.69	.;.;.;D;D;D;.;.;D;.
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D;D;.;.
M_CAP	Benign	0.072	D
MetaRNN	Pathogenic	0.83	D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.68	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-5.5	D;D;D;D;D;D;D;D;D;D
REVEL	Uncertain	0.59
Sift	Benign	0.063	T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.20	T;T;T;T;T;T;T;T;T;T
Polyphen		0.86	P;P;P;B;P;B;.;.;B;P
Vest4		0.92
MutPred		0.51		.;.;.;.;Gain of MoRF binding (P = 0.0153);.;.;.;.;.;
MVP		0.54
MPC		2.1
ClinPred		0.99	D
GERP RS		5.2
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs193921019; hg19: chr9-73213568; COSMIC: COSV62593869;