Variant 9-70536345-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP2

The NM_001366145.2(TRPM3):c.4768G>T(p.Asp1590Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,834 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

TRPM3
NM_001366145.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.38

Variant links:

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]

TRPM3 links:

KLF9-DT (HGNC:):

KLF9-DT links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRPM3	NM_001366145.2 linkuse as main transcript	c.4768G>T	p.Asp1590Tyr	missense_variant	26/26	ENST00000677713.2	NP_001353074.1
KLF9-DT	XR_001746707.3 linkuse as main transcript	n.467-13934C>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRPM3	ENST00000677713.2 linkuse as main transcript	c.4768G>T	p.Asp1590Tyr	missense_variant	26/26		NM_001366145.2	ENSP00000503830	P4	Q9HCF6-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461834

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727214

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 01, 2024

The c.4732G>T (p.D1578Y) alteration is located in exon 25 (coding exon 25) of the TRPM3 gene. This alteration results from a G to T substitution at nucleotide position 4732, causing the aspartic acid (D) at amino acid position 1578 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Uncertain

0.0

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.13

.;.;T;T;T;.;.;T;.

Eigen

Uncertain

0.39

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

D;D;D;D;D;D;D;.;.

M_CAP

Benign

0.043

MetaRNN

Uncertain

0.47

T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.87

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;D;D;D;D

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-2.2

N;N;N;N;N;N;N;N;N

REVEL

Benign

0.27

Sift

Uncertain

0.0010

D;D;D;D;D;D;D;D;D

Sift4G

Uncertain

0.0040

D;D;D;D;D;D;D;D;D

Polyphen

0.98

D;D;D;D;D;.;.;D;D

Vest4

0.54

MutPred

0.39

.;.;.;Gain of sheet (P = 0.0028);.;.;.;.;.;

MVP

0.81

MPC

0.61

ClinPred

0.96

GERP RS

5.9

gMVP

0.77

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over