chr15-50570155-C-T

Variant names:

• chr15-50570155-C-T
• NM_017672.6:c.5309G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_017672.6(TRPM7):​c.5309G>A​(p.Gly1770Asp) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: TRPM7 NM_017672.6 missense, splice_region
• Scores: Splicing: ADA: 0.9997
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.97
• Publications: 0 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
• macrothrombocytopenia, isolated

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• amyotrophic lateral sclerosis-parkinsonism-dementia complex

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017672.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRPM7	NM_017672.6	MANE Select	c.5309G>A	p.Gly1770Asp	missense splice_region	Exon 37 of 39	NP_060142.3
	TRPM7	NM_001301212.2		c.5306G>A	p.Gly1769Asp	missense splice_region	Exon 37 of 39	NP_001288141.1	H0YLN8
	TRPM7	NR_149152.2		n.5523G>A		splice_region non_coding_transcript_exon	Exon 37 of 39

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRPM7	ENST00000646667.1	MANE Select	c.5309G>A	p.Gly1770Asp	missense splice_region	Exon 37 of 39	ENSP00000495860.1	Q96QT4
	TRPM7	ENST00000560955.5	TSL:1	c.5306G>A	p.Gly1769Asp	missense splice_region	Exon 37 of 39	ENSP00000453277.1	H0YLN8
	TRPM7	ENST00000561267.5	TSL:3	c.446G>A	p.Gly149Asp	missense splice_region	Exon 4 of 6	ENSP00000454066.1	H0YNM0

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.030	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.0079	D
MutationAssessor	Pathogenic	3.5	H
PhyloP100		6.0
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-4.3	D
REVEL	Uncertain	0.63
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.82
MutPred		0.94		Gain of relative solvent accessibility (P = 0.09)
MVP		0.60
MPC		0.64
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.80
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.83
SpliceAI score (max)		0.040		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

hg19: chr15-50862352; COSMIC: COSV106058747; COSMIC: COSV106058747;