15-50561374-A-G

Variant names:

• chr15-50561374-A-G
• rs616256
• NM_017672.6:c.*304T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_017672.6(TRPM7):​c.*304T>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 0.557 in 245,276 control chromosomes in the GnomAD database, including 38,442 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.55 (23511 hom., cov: 32)
  • Exomes 𝑓: 0.56 (14931 hom.)
• Consequence: TRPM7 NM_017672.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.433
• Publications: 12 publications found

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]

TRPM7 Gene-Disease associations (from GenCC):

• hypomagnesemia, seizures, and intellectual disability

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• autosomal dominant macrothrombocytopenia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• macrothrombocytopenia, isolated

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• amyotrophic lateral sclerosis-parkinsonism-dementia complex

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 15-50561374-A-G is Benign according to our data. Variant chr15-50561374-A-G is described in ClinVar as Benign. ClinVar VariationId is 1281710.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.612 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRPM7	NM_017672.6	c.*304T>C		3_prime_UTR_variant	Exon 39 of 39	ENST00000646667.1	NP_060142.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRPM7	ENST00000646667.1	c.*304T>C		3_prime_UTR_variant	Exon 39 of 39		NM_017672.6	ENSP00000495860.1
TRPM7	ENST00000560955.5	c.*304T>C		3_prime_UTR_variant	Exon 39 of 39	1		ENSP00000453277.1
TRPM7	ENST00000561267.5	c.604+8513T>C		intron_variant	Intron 5 of 5	3		ENSP00000454066.1

Frequencies

GnomAD3 genomes AF: 0.554 AC: 84223 AN: 151894 Hom.: 23494 Cov.: 32

Gnomad AFR AF: 0.540

Gnomad AMI AF: 0.602

Gnomad AMR AF: 0.622

Gnomad ASJ AF: 0.554

Gnomad EAS AF: 0.570

Gnomad SAS AF: 0.558

Gnomad FIN AF: 0.474

Gnomad MID AF: 0.598

Gnomad NFE AF: 0.557

Gnomad OTH AF: 0.594

GnomAD4 exome AF: 0.561 AC: 52296 AN: 93260 Hom.: 14931 Cov.: 2 AF XY: 0.562 AC XY: 26874 AN XY: 47822

African (AFR) AF: 0.541 AC: 1460 AN: 2698

American (AMR) AF: 0.609 AC: 2007 AN: 3298

Ashkenazi Jewish (ASJ) AF: 0.568 AC: 1932 AN: 3400

East Asian (EAS) AF: 0.571 AC: 3180 AN: 5570

South Asian (SAS) AF: 0.564 AC: 2882 AN: 5108

European-Finnish (FIN) AF: 0.496 AC: 2722 AN: 5492

Middle Eastern (MID) AF: 0.581 AC: 273 AN: 470

European-Non Finnish (NFE) AF: 0.564 AC: 34386 AN: 61000

Other (OTH) AF: 0.555 AC: 3454 AN: 6224

GnomAD4 genome AF: 0.554 AC: 84291 AN: 152016 Hom.: 23511 Cov.: 32 AF XY: 0.555 AC XY: 41209 AN XY: 74300

African (AFR) AF: 0.540 AC: 22398 AN: 41482

American (AMR) AF: 0.622 AC: 9499 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.554 AC: 1924 AN: 3472

East Asian (EAS) AF: 0.569 AC: 2943 AN: 5168

South Asian (SAS) AF: 0.559 AC: 2692 AN: 4820

European-Finnish (FIN) AF: 0.474 AC: 4992 AN: 10540

Middle Eastern (MID) AF: 0.602 AC: 177 AN: 294

European-Non Finnish (NFE) AF: 0.557 AC: 37869 AN: 67946

Other (OTH) AF: 0.591 AC: 1249 AN: 2112

Alfa AF: 0.562 Hom.: 67815

Bravo AF: 0.565

Asia WGS AF: 0.554 AC: 1925 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	2.3
DANN	Benign	0.66
PhyloP100		0.43
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs616256; hg19: chr15-50853571;