Genetic Variant MT1G:p.Ala62Thr (chr16-56666884-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001301267.2(MT1G):c.184G>A(p.Ala62Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000942 in 1,614,240 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000070 ( 0 hom. )

Consequence

MT1G
NM_001301267.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.348

Variant links:

Genes affected

MT1G (HGNC:7399): (metallothionein 1G) Enables zinc ion binding activity. Involved in cellular response to metal ion; cellular response to vascular endothelial growth factor stimulus; and negative regulation of growth. Located in cytoplasm and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

MT1G links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.028395474).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MT1G	NM_001301267.2 link	c.184G>A	p.Ala62Thr	missense_variant	Exon 3 of 3	ENST00000379811.4	NP_001288196.1	P13640-1
MT1G	NM_005950.3 link	c.181G>A	p.Ala61Thr	missense_variant	Exon 3 of 3		NP_005941.1	P13640-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MT1G	ENST00000379811.4 link	c.184G>A	p.Ala62Thr	missense_variant	Exon 3 of 3	1	NM_001301267.2	ENSP00000369139.4	P13640-1
MT1G	ENST00000444837.6 link	c.181G>A	p.Ala61Thr	missense_variant	Exon 3 of 3	1		ENSP00000391397.2	P13640-2
MT1G	ENST00000568675.1 link	n.550G>A		non_coding_transcript_exon_variant	Exon 2 of 2	1
MT1G	ENST00000569500.5 link	c.115G>A	p.Ala39Thr	missense_variant	Exon 2 of 2	3		ENSP00000456675.1	H3BSF1

Frequencies

GnomAD3 genomes

AF:

0.000328

AC:

AN:

152258

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00106

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000107

AC:

AN:

251350

Hom.:

AF XY:

0.000103

AC XY:

AN XY:

135840

show subpopulations

Gnomad AFR exome

AF:

0.000984

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000616

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000698

AC:

102

AN:

1461864

Hom.:

Cov.:

AF XY:

0.0000701

AC XY:

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.00105

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.000115

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000396

Gnomad4 OTH exome

AF:

0.000182

GnomAD4 genome

AF:

0.000328

AC:

AN:

152376

Hom.:

Cov.:

AF XY:

0.000322

AC XY:

AN XY:

74512

show subpopulations

Gnomad4 AFR

AF:

0.00106

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000192

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000126

Hom.:

Bravo

AF:

0.000340

ESP6500AA

AF:

0.000682

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000123

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 17, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.181G>A (p.A61T) alteration is located in exon 3 (coding exon 3) of the MT1G gene. This alteration results from a G to A substitution at nucleotide position 181, causing the alanine (A) at amino acid position 61 to be replaced by a threonine (T). 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

0.16

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.66

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.25

.;.;T

Eigen

Benign

-0.39

Eigen_PC

Benign

-0.49

FATHMM_MKL

Benign

0.031

LIST_S2

Uncertain

0.96

D;D;D

M_CAP

Benign

0.038

MetaRNN

Benign

0.028

T;T;T

MetaSVM

Benign

-1.0

PROVEAN

Benign

-2.1

N;D;N

REVEL

Benign

0.054

Sift

Uncertain

0.0010

D;D;D

Sift4G

Uncertain

0.0060

D;D;D

Polyphen

0.71

P;.;.

Vest4

0.099

MVP

0.014

MPC

0.0021

ClinPred

0.046

GERP RS

1.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.13

gMVP

0.022

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