Genetic Variant NM_005946.3:c.29-28A>G (chr16-56639236-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_005946.3(MT1A):c.29-28A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.719 in 1,608,540 control chromosomes in the GnomAD database, including 418,039 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.67 ( 34550 hom., cov: 34)

Exomes 𝑓: 0.72 ( 383489 hom. )

Consequence

MT1A
NM_005946.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.04

Publications

33 publications found

Variant links:

Genes affected

MT1A (HGNC:7393): (metallothionein 1A) This gene is a member of the metallothionein family of genes. Proteins encoded by this gene family are low in molecular weight, are cysteine-rich, lack aromatic residues, and bind divalent heavy metal ions. The conserved cysteine residues co-ordinate metal ions using mercaptide linkages. These proteins act as anti-oxidants, protect against hydroxyl free radicals, are important in homeostatic control of metal in the cell, and play a role in detoxification of heavy metals. Disruption of two metallothionein genes in mouse resulted in defects in protection against heavy metals, oxidative stress, immune reactions, carcinogens, and displayed obesity. [provided by RefSeq, Sep 2017]

MT1A links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.96).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.73 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MT1A	NM_005946.3 link	c.29-28A>G		intron_variant	Intron 1 of 2	ENST00000290705.12	NP_005937.2	P04731

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MT1A	ENST00000290705.12 link	c.29-28A>G		intron_variant	Intron 1 of 2	1	NM_005946.3	ENSP00000290705.8		P04731

Frequencies

GnomAD3 genomes

AF:

0.669

AC:

101508

AN:

151772

Hom.:

34545

Cov.:

show subpopulations

Gnomad AFR

AF:

0.521

Gnomad AMI

AF:

0.610

Gnomad AMR

AF:

0.706

Gnomad ASJ

AF:

0.737

Gnomad EAS

AF:

0.661

Gnomad SAS

AF:

0.684

Gnomad FIN

AF:

0.735

Gnomad MID

AF:

0.768

Gnomad NFE

AF:

0.736

Gnomad OTH

AF:

0.688

GnomAD2 exomes

AF:

0.707

AC:

177397

AN:

250804

AF XY:

0.712

show subpopulations

Gnomad AFR exome

AF:

0.523

Gnomad AMR exome

AF:

0.686

Gnomad ASJ exome

AF:

0.737

Gnomad EAS exome

AF:

0.655

Gnomad FIN exome

AF:

0.734

Gnomad NFE exome

AF:

0.740

Gnomad OTH exome

AF:

0.727

GnomAD4 exome

AF:

0.724

AC:

1055031

AN:

1456650

Hom.:

383489

Cov.:

AF XY:

0.725

AC XY:

525176

AN XY:

724750

show subpopulations

African (AFR)

AF:

0.519

AC:

17325

AN:

33392

American (AMR)

AF:

0.691

AC:

30736

AN:

44492

Ashkenazi Jewish (ASJ)

AF:

0.733

AC:

19018

AN:

25940

East Asian (EAS)

AF:

0.705

AC:

27922

AN:

39584

South Asian (SAS)

AF:

0.700

AC:

60320

AN:

86170

European-Finnish (FIN)

AF:

0.734

AC:

38920

AN:

52998

Middle Eastern (MID)

AF:

0.788

AC:

4291

AN:

5446

European-Non Finnish (NFE)

AF:

0.734

AC:

813900

AN:

1108640

Other (OTH)

AF:

0.710

AC:

42599

AN:

59988

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

14323

28646

42968

57291

71614

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19996

39992

59988

79984

99980

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.668

AC:

101535

AN:

151890

Hom.:

34550

Cov.:

AF XY:

0.671

AC XY:

49779

AN XY:

74240

show subpopulations

African (AFR)

AF:

0.521

AC:

21546

AN:

41384

American (AMR)

AF:

0.706

AC:

10789

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.737

AC:

2555

AN:

3468

East Asian (EAS)

AF:

0.661

AC:

3411

AN:

5162

South Asian (SAS)

AF:

0.686

AC:

3311

AN:

4830

European-Finnish (FIN)

AF:

0.735

AC:

7758

AN:

10552

Middle Eastern (MID)

AF:

0.760

AC:

222

AN:

292

European-Non Finnish (NFE)

AF:

0.736

AC:

49941

AN:

67890

Other (OTH)

AF:

0.685

AC:

1449

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1714

3428

5141

6855

8569

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

802

1604

2406

3208

4010

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.686

Hom.:

5074

Bravo

AF:

0.663

Asia WGS

AF:

0.669

AC:

2327

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.96

CADD

Benign

0.23

(source)

DANN

Benign

0.72

PhyloP100

-2.0

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over