NM_001366145.2:c.5026C>T

Variant names:

• chr9-70536087-G-A
• rs41287375
• NM_001366145.2:c.5026C>T

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_001366145.2(TRPM3):​c.5026C>T​(p.Arg1676Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00015 in 1,614,202 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1676Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (2 hom.)
• Consequence: TRPM3 NM_001366145.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 1.60
• Publications: 4 publications found

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]

ENSG00000308298 (HGNC:):

KLF9-DT (HGNC:54815): (KLF9 divergent transcript)

ACMG classification

Our verdict: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.097322345).
• BP6: Variant 9-70536087-G-A is Benign according to our data. Variant chr9-70536087-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2515734.
• BS2: High AC in GnomAd4 at 18 AD,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001366145.2. 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
	TRPM3	NM_001366145.2	MANE Select	c.5026C>T	p.Arg1676Trp	missense	Exon 26 of 26	NP_001353074.1	Q9HCF6-3
	TRPM3	NM_001366147.2		c.5101C>T	p.Arg1701Trp	missense	Exon 27 of 27	NP_001353076.1
	TRPM3	NM_001366141.2		c.4996C>T	p.Arg1666Trp	missense	Exon 25 of 25	NP_001353070.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRPM3	ENST00000677713.2	MANE Select	c.5026C>T	p.Arg1676Trp	missense	Exon 26 of 26	ENSP00000503830.2	Q9HCF6-3
	TRPM3	ENST00000377110.9	TSL:1	c.4990C>T	p.Arg1664Trp	missense	Exon 25 of 25	ENSP00000366314.4	Q9HCF6-2
	TRPM3	ENST00000377111.8	TSL:1	c.3956-636C>T		intron	N/A	ENSP00000366315.4	Q9HCF6-10

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152202 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000187 AC: 47 AN: 251486 AF XY: 0.000206

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000260

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000149

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000153 AC: 224 AN: 1461882 Hom.: 2 Cov.: 82 AF XY: 0.000188 AC XY: 137 AN XY: 727238

African (AFR) AF: 0.0000896 AC: 3 AN: 33480

American (AMR) AF: 0.000201 AC: 9 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000742 AC: 64 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00156 AC: 9 AN: 5766

European-Non Finnish (NFE) AF: 0.000112 AC: 124 AN: 1112004

Other (OTH) AF: 0.000232 AC: 14 AN: 60396

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152320 Hom.: 0 Cov.: 32 AF XY: 0.000188 AC XY: 14 AN XY: 74472

African (AFR) AF: 0.0000481 AC: 2 AN: 41576

American (AMR) AF: 0.000196 AC: 3 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000580 AC: 3 AN: 5174

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68032

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000149 Hom.: 0

Bravo AF: 0.000136

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000198 AC: 24

EpiCase AF: 0.000164

EpiControl AF: 0.000356

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.097	T
MetaSVM	Benign	-0.64	T
PhyloP100		1.6
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.21
Sift	Benign	0.037	D
Sift4G	Benign	0.19	T
Polyphen		1.0	D
Vest4		0.44
MVP		0.74
MPC		0.49
ClinPred		0.13	T
GERP RS		3.9
gMVP		0.50
Mutation Taster		=61/39	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

dbSNP: rs41287375; hg19: chr9-73151003; COSMIC: COSV62593035;