rs6560142

Positions:

• chr9-70536068-C-A
• chr9-70536068-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.5045G>T​(p.Arg1682Leu) 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. 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. R1682Q) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TRPM3 NM_001366145.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.57

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]

KLF9-DT (HGNC:):

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, 0.761

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRPM3	NM_001366145.2	c.5045G>T	p.Arg1682Leu	missense_variant	26/26	ENST00000677713.2
KLF9-DT	XR_001746707.3	n.467-14211C>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRPM3	ENST00000677713.2	c.5045G>T	p.Arg1682Leu	missense_variant	26/26		NM_001366145.2	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 84

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	.;.;T;T;T;.;.;T;.
Eigen	Uncertain	0.60
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D;D;.;.
M_CAP	Benign	0.055	D
MetaRNN	Pathogenic	0.76	D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.54	T
MutationTaster	Benign	0.000040	P;P;P;P;P;P;P;P;P;P;P
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-1.9	N;N;N;N;N;N;N;N;N
REVEL	Benign	0.26
Sift	Uncertain	0.0080	D;D;D;D;D;D;D;D;D
Sift4G	Benign	0.072	T;T;T;T;T;T;T;T;T
Polyphen		1.0	D;D;D;B;D;.;.;D;D
Vest4		0.61
MutPred		0.22		.;.;.;Gain of helix (P = 0.0425);.;.;.;.;.;
MVP		0.60
MPC		0.61
ClinPred		0.96	D
GERP RS		5.8
gMVP		0.54

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

Publications

LitVar

Other links and lift over

dbSNP: rs6560142; hg19: chr9-73150984;