15-50586433-G-A

Position:

chr15-50586433-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

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. 14/20 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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

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

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/exons	MANE	UniProt
TRPM7	NM_017672.6 linkuse as main transcript	c.4445C>T	p.Thr1482Ile	missense_variant	28/39	ENST00000646667.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
TRPM7	ENST00000646667.1 linkuse as main transcript	c.4445C>T	p.Thr1482Ile	missense_variant	28/39		NM_017672.6	A1
TRPM7	ENST00000560955.5 linkuse as main transcript	c.4445C>T	p.Thr1482Ile	missense_variant	28/39	1		P4
TRPM7	ENST00000560849.2 linkuse as main transcript	n.150C>T		non_coding_transcript_exon_variant	1/6	3
TRPM7	ENST00000645282.1 linkuse as main transcript	n.249C>T		non_coding_transcript_exon_variant	3/4

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

GnomAD3 exomes

AF:

0.0847

AC:

21066

AN:

248672

Hom.:

1059

AF XY:

0.0883

AC XY:

11916

AN XY:

134914

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 SAS exome

AF:

0.113

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

Gnomad4 AFR exome

AF:

0.0163

Gnomad4 AMR exome

AF:

0.0587

Gnomad4 ASJ exome

AF:

0.0692

Gnomad4 EAS exome

AF:

0.138

Gnomad4 SAS exome

AF:

0.107

Gnomad4 FIN exome

AF:

0.0548

Gnomad4 NFE exome

AF:

0.107

Gnomad4 OTH exome

AF:

0.0999

GnomAD4 genome

AF:

0.0751

AC:

11440

AN:

152312

Hom.:

558

Cov.:

AF XY:

0.0737

AC XY:

5489

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.0215

Gnomad4 AMR

AF:

0.0644

Gnomad4 ASJ

AF:

0.0793

Gnomad4 EAS

AF:

0.0980

Gnomad4 SAS

AF:

0.122

Gnomad4 FIN

AF:

0.0531

Gnomad4 NFE

AF:

0.108

Gnomad4 OTH

AF:

0.0804

Alfa

AF:

0.0975

Hom.:

1535

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

Uncertain significance, criteria provided, single submitter

research

Suna and Inan Kirac Foundation Neurodegeneration Research Laboratory, Koc University

Mar 31, 2020

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 12, 2018

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

TRPM7-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 18, 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). -

Amyotrophic lateral sclerosis-parkinsonism/dementia complex 1, susceptibility to

Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Jan 05, 2010

- -

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

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

0.59

.;T;T

MetaRNN

Benign

0.0015

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.90

L;L;.

MutationTaster

Benign

0.72

P;P

PrimateAI

Benign

0.36

PROVEAN

Benign

-1.4

.;N;N

REVEL

Benign

0.037

Sift

Benign

0.25

.;T;D

Sift4G

Benign

0.12

.;T;T

Polyphen

0.19

B;B;.

Vest4

0.014, 0.024

MPC

0.13

ClinPred

0.0096

GERP RS

2.2

Varity_R

0.020

gMVP

0.34

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over