15-50586433-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The NM_017672.6(TRPM7):c.4445C>T(p.Thr1482Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0988 in 1,611,142 control chromosomes in the GnomAD database, including 8,758 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.075 ( 558 hom., cov: 32)

Exomes 𝑓: 0.10 ( 8200 hom. )

Consequence

TRPM7
NM_017672.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2O:1

Conservation

PhyloP100: 1.99

Publications

65 publications found

Variant links:

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)

TRPM7 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0014967024).

BP6

Variant 15-50586433-G-A is Benign according to our data. Variant chr15-50586433-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 4807.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.114 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRPM7	NM_017672.6 link	c.4445C>T	p.Thr1482Ile	missense_variant	Exon 28 of 39	ENST00000646667.1	NP_060142.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
TRPM7	ENST00000646667.1 link	c.4445C>T	p.Thr1482Ile	missense_variant	Exon 28 of 39		NM_017672.6	ENSP00000495860.1
TRPM7	ENST00000560955.5 link	c.4445C>T	p.Thr1482Ile	missense_variant	Exon 28 of 39	1		ENSP00000453277.1
TRPM7	ENST00000560849.2 link	n.150C>T		non_coding_transcript_exon_variant	Exon 1 of 6	3
TRPM7	ENST00000645282.1 link	n.249C>T		non_coding_transcript_exon_variant	Exon 3 of 4

Frequencies

GnomAD3 genomes

AF:

0.0751

AC:

11434

AN:

152194

Hom.:

556

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0215

Gnomad AMI

AF:

0.0768

Gnomad AMR

AF:

0.0643

Gnomad ASJ

AF:

0.0793

Gnomad EAS

AF:

0.0983

Gnomad SAS

AF:

0.123

Gnomad FIN

AF:

0.0531

Gnomad MID

AF:

0.0949

Gnomad NFE

AF:

0.108

Gnomad OTH

AF:

0.0760

GnomAD2 exomes

AF:

0.0847

AC:

21066

AN:

248672

AF XY:

0.0883

show subpopulations

Gnomad AFR exome

AF:

0.0177

Gnomad AMR exome

AF:

0.0583

Gnomad ASJ exome

AF:

0.0755

Gnomad EAS exome

AF:

0.0725

Gnomad FIN exome

AF:

0.0529

Gnomad NFE exome

AF:

0.103

Gnomad OTH exome

AF:

0.0868

GnomAD4 exome

AF:

0.101

AC:

147740

AN:

1458830

Hom.:

8200

Cov.:

AF XY:

0.102

AC XY:

73890

AN XY:

725808

show subpopulations

African (AFR)

AF:

0.0163

AC:

546

AN:

33456

American (AMR)

AF:

0.0587

AC:

2623

AN:

44672

Ashkenazi Jewish (ASJ)

AF:

0.0692

AC:

1807

AN:

26098

East Asian (EAS)

AF:

0.138

AC:

5474

AN:

39588

South Asian (SAS)

AF:

0.107

AC:

9251

AN:

86080

European-Finnish (FIN)

AF:

0.0548

AC:

2926

AN:

53366

Middle Eastern (MID)

AF:

0.0875

AC:

504

AN:

5762

European-Non Finnish (NFE)

AF:

0.107

AC:

118589

AN:

1109552

Other (OTH)

AF:

0.0999

AC:

6020

AN:

60256

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.452

Heterozygous variant carriers

5780

11560

17339

23119

28899

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4272

8544

12816

17088

21360

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0751

AC:

11440

AN:

152312

Hom.:

558

Cov.:

AF XY:

0.0737

AC XY:

5489

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.0215

AC:

893

AN:

41590

American (AMR)

AF:

0.0644

AC:

986

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0793

AC:

275

AN:

3468

East Asian (EAS)

AF:

0.0980

AC:

508

AN:

5186

South Asian (SAS)

AF:

0.122

AC:

589

AN:

4826

European-Finnish (FIN)

AF:

0.0531

AC:

564

AN:

10614

Middle Eastern (MID)

AF:

0.0952

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.108

AC:

7357

AN:

68006

Other (OTH)

AF:

0.0804

AC:

170

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

545

1090

1635

2180

2725

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

142

284

426

568

710

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0939

Hom.:

2048

Bravo

AF:

0.0708

TwinsUK

AF:

0.105

AC:

389

ALSPAC

AF:

0.109

AC:

420

ESP6500AA

AF:

0.0182

AC:

ESP6500EA

AF:

0.107

AC:

879

ExAC

AF:

0.0861

AC:

10405

Asia WGS

AF:

0.144

AC:

499

AN:

3478

EpiCase

AF:

0.106

EpiControl

AF:

0.107

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Juvenile amyotrophic lateral sclerosis

Uncertain:1

Mar 31, 2020

Suna and Inan Kirac Foundation Neurodegeneration Research Laboratory, Koc University

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

not provided

Benign:1

Nov 12, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 16051700, 25681989, 29874175, 32579787)

TRPM7-related disorder

Benign:1

Aug 26, 2024

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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).

AMYOTROPHIC LATERAL SCLEROSIS-PARKINSONISM/DEMENTIA COMPLEX 1, SUSCEPTIBILITY TO

Other:1

Jan 05, 2010

OMIM

Significance:risk factor

Review Status:no assertion criteria provided

Collection Method:literature only

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.58

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.20

T;T;T

Eigen

Benign

-0.34

Eigen_PC

Benign

-0.23

FATHMM_MKL

Benign

0.74

LIST_S2

Benign

0.0

.;T;T

MetaRNN

Benign

0.0015

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.90

L;L;.

PhyloP100

2.0

PrimateAI

Benign

0.36

PROVEAN

Benign

0.0

.;N;N

REVEL

Benign

0.0

Sift

Pathogenic

0.0

.;T;D

Sift4G

Pathogenic

0.0

.;T;T

Vest4

0.0

ClinPred

0.0096

GERP RS

2.2

Varity_R

0.020

gMVP

0.34

Mutation Taster

=80/20

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over