Genetic Variant TRPM7:p.Asp1839Asn (chr15-50561761-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_017672.6(TRPM7):c.5515G>A(p.Asp1839Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000509 in 1,612,480 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000053 ( 0 hom. )

Consequence

TRPM7
NM_017672.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.37

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.20347127).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRPM7	NM_017672.6 link	c.5515G>A	p.Asp1839Asn	missense_variant	Exon 39 of 39	ENST00000646667.1	NP_060142.3	Q96QT4A0A024R5V1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TRPM7	ENST00000646667.1 link	c.5515G>A	p.Asp1839Asn	missense_variant	Exon 39 of 39		NM_017672.6	ENSP00000495860.1	Q96QT4
TRPM7	ENST00000560955.5 link	c.5512G>A	p.Asp1838Asn	missense_variant	Exon 39 of 39	1		ENSP00000453277.1	H0YLN8
TRPM7	ENST00000561267.5 link	c.604+8126G>A		intron_variant	Intron 5 of 5	3		ENSP00000454066.1	H0YNM0
TRPM7	ENST00000561443.5 link	n.1072G>A		non_coding_transcript_exon_variant	Exon 10 of 10	2

Frequencies

GnomAD3 genomes

AF:

0.0000330

AC:

AN:

151452

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.000481

GnomAD3 exomes

AF:

0.00000803

AC:

AN:

248960

Hom.:

AF XY:

0.00000740

AC XY:

AN XY:

135088

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000527

AC:

AN:

1461028

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

726802

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000666

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000330

AC:

AN:

151452

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

73874

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.000481

Alfa

AF:

0.0000579

Hom.:

Bravo

AF:

0.0000453

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000123

AC:

ExAC

AF:

0.0000166

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 14, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.5515G>A (p.D1839N) alteration is located in exon 39 (coding exon 39) of the TRPM7 gene. This alteration results from a G to A substitution at nucleotide position 5515, causing the aspartic acid (D) at amino acid position 1839 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.53

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.14

T;T;T

Eigen

Uncertain

0.32

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.75

.;T;T

M_CAP

Benign

0.020

MetaRNN

Benign

0.20

T;T;T

MetaSVM

Benign

-0.89

MutationAssessor

Benign

1.4

L;L;.

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-0.41

.;N;N

REVEL

Benign

0.12

Sift

Uncertain

0.013

.;D;D

Sift4G

Uncertain

0.036

.;D;D

Polyphen

0.80

P;P;.

Vest4

0.34, 0.24

MVP

0.53

MPC

0.16

ClinPred

0.63

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.068

gMVP

0.43

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

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