Genetic Variant MT1G:p.Ala17Thr (chr16-56667360-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.49G>A(p.Ala17Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000477 in 1,614,086 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000047 ( 1 hom. )

Consequence

MT1G
NM_001301267.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.605

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:

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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=0.05184096).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MT1G	NM_001301267.2 link	c.49G>A	p.Ala17Thr	missense_variant	Exon 2 of 3	ENST00000379811.4	NP_001288196.1	P13640-1
MT1G	NM_005950.3 link	c.46G>A	p.Ala16Thr	missense_variant	Exon 2 of 3		NP_005941.1	P13640-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MT1G	ENST00000379811.4 link	c.49G>A	p.Ala17Thr	missense_variant	Exon 2 of 3	1	NM_001301267.2	ENSP00000369139.4	P13640-1
MT1G	ENST00000444837.6 link	c.46G>A	p.Ala16Thr	missense_variant	Exon 2 of 3	1		ENSP00000391397.2	P13640-2
MT1G	ENST00000568675.1 link	n.74G>A		non_coding_transcript_exon_variant	Exon 2 of 2	1
MT1G	ENST00000569500.5 link	c.29-390G>A		intron_variant	Intron 1 of 1	3		ENSP00000456675.1	H3BSF1

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

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:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000438

AC:

AN:

251424

Hom.:

AF XY:

0.0000368

AC XY:

AN XY:

135910

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.0000867

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000465

AC:

AN:

1461892

Hom.:

Cov.:

AF XY:

0.0000523

AC XY:

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000134

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000126

Gnomad4 SAS exome

AF:

0.000104

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000369

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.0000591

AC:

AN:

152194

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.0000965

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:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000115

Hom.:

Bravo

AF:

0.0000718

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.000164

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

Feb 10, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.46G>A (p.A16T) alteration is located in exon 2 (coding exon 2) of the MT1G gene. This alteration results from a G to A substitution at nucleotide position 46, causing the alanine (A) at amino acid position 16 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

0.074

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.75

CADD

Benign

5.7

DANN

Benign

0.75

DEOGEN2

Benign

0.23

.;T;T

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.61

T;T;T

M_CAP

Benign

0.0023

MetaRNN

Benign

0.052

T;T;T

MetaSVM

Benign

-1.0

PROVEAN

Uncertain

-2.8

D;D;N

REVEL

Benign

0.031

Sift

Benign

0.087

T;T;T

Sift4G

Benign

0.27

T;T;T

Polyphen

0.0010

B;.;.

Vest4

0.15

MVP

0.014

MPC

0.0021

ClinPred

0.046

GERP RS

-0.56

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.0

Varity_R

0.085

gMVP

0.058

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