15-31001375-C-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001252024.2(TRPM1):c.*447G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0139 in 161,024 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.014 (36 hom., cov: 31)
  • Exomes 𝑓: 0.0095 (1 hom.)
• Consequence: TRPM1 NM_001252024.2 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.822

Genes affected

TRPM1 (HGNC:7146): (transient receptor potential cation channel subfamily M member 1) This gene encodes a member of the transient receptor potential melastatin subfamily of transient receptor potential ion channels. The encoded protein is a calcium permeable cation channel that is expressed in melanocytes and may play a role in melanin synthesis. Specific mutations in this gene are the cause autosomal recessive complete congenital stationary night blindness-1C. The expression of this protein is inversely correlated with melanoma aggressiveness and as such it is used as a prognostic marker for melanoma metastasis. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Oct 2011]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 15-31001375-C-G is Benign according to our data. Variant chr15-31001375-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 315483.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0142 (2138/150866) while in subpopulation NFE AF= 0.0183 (1242/67862). AF 95% confidence interval is 0.0175. There are 36 homozygotes in gnomad4. There are 1107 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 36 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRPM1	NM_001252024.2	c.*447G>C		3_prime_UTR_variant	28/28	ENST00000256552.11
TRPM1	NM_001252020.2	c.*447G>C		3_prime_UTR_variant	27/27
TRPM1	NM_002420.6	c.*447G>C		3_prime_UTR_variant	27/27

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRPM1	ENST00000256552.11	c.*447G>C		3_prime_UTR_variant	28/28	1	NM_001252024.2	P4
	ENST00000665655.1	n.71+9134C>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0142 AC: 2138 AN: 150746 Hom.: 36 Cov.: 31

Gnomad AFR AF: 0.00256

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0108

Gnomad ASJ AF: 0.00577

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00168

Gnomad FIN AF: 0.0578

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0183

Gnomad OTH AF: 0.00629

GnomAD4 exome AF: 0.00945 AC: 96 AN: 10158 Hom.: 1 Cov.: 0 AF XY: 0.0102 AC XY: 57 AN XY: 5594

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00503

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00233

Gnomad4 FIN exome AF: 0.0187

Gnomad4 NFE exome AF: 0.0125

Gnomad4 OTH exome AF: 0.00439

GnomAD4 genome AF: 0.0142 AC: 2138 AN: 150866 Hom.: 36 Cov.: 31 AF XY: 0.0150 AC XY: 1107 AN XY: 73556

Gnomad4 AFR AF: 0.00256

Gnomad4 AMR AF: 0.0108

Gnomad4 ASJ AF: 0.00577

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00168

Gnomad4 FIN AF: 0.0578

Gnomad4 NFE AF: 0.0183

Gnomad4 OTH AF: 0.00623

Alfa AF: 0.0192 Hom.: 4

Bravo AF: 0.0101

Asia WGS AF: 0.00115 AC: 6 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Congenital stationary night blindness 1C Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
Cadd	Benign	0.71
Dann	Benign	0.64

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: rs35415636; hg19: chr15-31293578;