15-50570160-A-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_017672.6(TRPM7):c.5309-5T>C variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00993 in 1,584,076 control chromosomes in the GnomAD database, including 109 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0065 (7 hom., cov: 31)
  • Exomes 𝑓: 0.010 (102 hom.)
• Consequence: TRPM7 NM_017672.6 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0001167
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.63

Genes affected

TRPM7 (HGNC:17994): (transient receptor potential cation channel subfamily M member 7) This gene belongs to the melastatin subfamily of transient receptor potential family of ion channels. The protein encoded by this gene is both an ion channel and a serine/threonine protein kinase. The kinase activity is essential for the ion channel function, which serves to increase intracellular calcium levels and to help regulate magnesium ion homeostasis. The encoded protein is involved in cytoskeletal organization, cell adhesion, cell migration and organogenesis. Defects in this gene are a cause of amyotrophic lateral sclerosis-parkinsonism/dementia complex of Guam. The gene may also be associated with defects of cardiac function. [provided by RefSeq, Aug 2017]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 15-50570160-A-G is Benign according to our data. Variant chr15-50570160-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 2645329.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-50570160-A-G is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd at 7 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRPM7	NM_017672.6	c.5309-5T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000646667.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRPM7	ENST00000646667.1	c.5309-5T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NM_017672.6	A1

Frequencies

GnomAD3 genomes AF: 0.00652 AC: 992 AN: 152186 Hom.: 7 Cov.: 31

Gnomad AFR AF: 0.00217

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00210

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.0159

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0101

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00656 AC: 1546 AN: 235820 Hom.: 12 AF XY: 0.00636 AC XY: 817 AN XY: 128370

Gnomad AFR exome AF: 0.00155

Gnomad AMR exome AF: 0.00238

Gnomad ASJ exome AF: 0.000106

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00177

Gnomad FIN exome AF: 0.0176

Gnomad NFE exome AF: 0.00922

Gnomad OTH exome AF: 0.00472

GnomAD4 exome AF: 0.0103 AC: 14733 AN: 1431772 Hom.: 102 Cov.: 28 AF XY: 0.00992 AC XY: 7069 AN XY: 712296

Gnomad4 AFR exome AF: 0.00130

Gnomad4 AMR exome AF: 0.00236

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00203

Gnomad4 FIN exome AF: 0.0158

Gnomad4 NFE exome AF: 0.0119

Gnomad4 OTH exome AF: 0.00902

GnomAD4 genome AF: 0.00651 AC: 991 AN: 152304 Hom.: 7 Cov.: 31 AF XY: 0.00651 AC XY: 485 AN XY: 74468

Gnomad4 AFR AF: 0.00216

Gnomad4 AMR AF: 0.00209

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00187

Gnomad4 FIN AF: 0.0159

Gnomad4 NFE AF: 0.0100

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00826 Hom.: 4

Bravo AF: 0.00542

Asia WGS AF: 0.000289 AC: 1 AN: 3470

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

May 01, 2023

TRPM7: BP4, BS2 -

TRPM7-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 12, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
Cadd	Benign	3.6
Dann	Benign	0.52

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00012
dbscSNV1_RF	Benign	0.094
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: rs117899712; hg19: chr15-50862357;