Genetic Variant MT1A:c.*249C>G (chr16-56640199-C-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.*249C>G variant causes a downstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.606 in 430,188 control chromosomes in the GnomAD database, including 82,734 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 0.54 ( 24263 hom., cov: 33)

Exomes 𝑓: 0.64 ( 58471 hom. )

Consequence

MT1A
NM_005946.3 downstream_gene

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0320

Publications

8 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=-0.84).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.646 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005946.3. 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
	MT1A	NM_005946.3	MANE Select	c.*249C>G		downstream_gene	N/A	NP_005937.2	P04731

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
MT1A	ENST00000290705.12	TSL:1 MANE Select	c.*249C>G	downstream_gene	N/A	ENSP00000290705.8	P04731
MT1A	ENST00000908024.1		c.*249C>G	downstream_gene	N/A	ENSP00000578083.1
MT1A	ENST00000927706.1		c.*249C>G	downstream_gene	N/A	ENSP00000597765.1

Frequencies

GnomAD3 genomes

AF:

0.541

AC:

82224

AN:

151912

Hom.:

24257

Cov.:

show subpopulations

Gnomad AFR

AF:

0.290

Gnomad AMI

AF:

0.565

Gnomad AMR

AF:

0.614

Gnomad ASJ

AF:

0.620

Gnomad EAS

AF:

0.486

Gnomad SAS

AF:

0.518

Gnomad FIN

AF:

0.714

Gnomad MID

AF:

0.634

Gnomad NFE

AF:

0.651

Gnomad OTH

AF:

0.569

GnomAD4 exome

AF:

0.642

AC:

178533

AN:

278156

Hom.:

58471

AF XY:

0.638

AC XY:

92154

AN XY:

144546

show subpopulations

African (AFR)

AF:

0.304

AC:

2522

AN:

8294

American (AMR)

AF:

0.636

AC:

6913

AN:

10862

Ashkenazi Jewish (ASJ)

AF:

0.651

AC:

5175

AN:

7950

East Asian (EAS)

AF:

0.586

AC:

9387

AN:

16006

South Asian (SAS)

AF:

0.541

AC:

12999

AN:

24038

European-Finnish (FIN)

AF:

0.726

AC:

9036

AN:

12444

Middle Eastern (MID)

AF:

0.671

AC:

1052

AN:

1568

European-Non Finnish (NFE)

AF:

0.670

AC:

121497

AN:

181306

Other (OTH)

AF:

0.634

AC:

9952

AN:

15688

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.524

Heterozygous variant carriers

2943

5886

8828

11771

14714

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1038

2076

3114

4152

5190

<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:

0.541

AC:

82241

AN:

152032

Hom.:

24263

Cov.:

AF XY:

0.545

AC XY:

40534

AN XY:

74326

show subpopulations

African (AFR)

AF:

0.290

AC:

12017

AN:

41464

American (AMR)

AF:

0.614

AC:

9366

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.620

AC:

2151

AN:

3468

East Asian (EAS)

AF:

0.486

AC:

2517

AN:

5174

South Asian (SAS)

AF:

0.520

AC:

2500

AN:

4812

European-Finnish (FIN)

AF:

0.714

AC:

7554

AN:

10574

Middle Eastern (MID)

AF:

0.626

AC:

184

AN:

294

European-Non Finnish (NFE)

AF:

0.651

AC:

44246

AN:

67968

Other (OTH)

AF:

0.566

AC:

1193

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1751

3501

5252

7002

8753

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

698

1396

2094

2792

3490

<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:

0.483

Hom.:

1569

Bravo

AF:

0.525

Asia WGS

AF:

0.516

AC:

1794

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

2.3

(source)

DANN

Benign

0.57

PhyloP100

0.032

Mutation Taster

=95/5

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over