NM_005946.3:c.80C>A

Variant names:

• chr16-56639315-C-A
• rs11640851
• NM_005946.3:c.80C>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005946.3(MT1A):​c.80C>A​(p.Thr27Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.623 in 1,609,960 control chromosomes in the GnomAD database, including 318,735 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 0.54 (24159 hom., cov: 34)
  • Exomes 𝑓: 0.63 (294576 hom.)
• Consequence: MT1A NM_005946.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.16
• Publications: 52 publications found

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]

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=3.2981764E-6).
• 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MT1A	NM_005946.3	MANE Select	c.80C>A	p.Thr27Asn	missense	Exon 2 of 3	NP_005937.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MT1A	ENST00000290705.12	TSL:1 MANE Select	c.80C>A	p.Thr27Asn	missense	Exon 2 of 3	ENSP00000290705.8

Frequencies

GnomAD3 genomes AF: 0.540 AC: 81938 AN: 151848 Hom.: 24154 Cov.: 34

Gnomad AFR AF: 0.286

Gnomad AMI AF: 0.562

Gnomad AMR AF: 0.610

Gnomad ASJ AF: 0.620

Gnomad EAS AF: 0.485

Gnomad SAS AF: 0.518

Gnomad FIN AF: 0.714

Gnomad MID AF: 0.636

Gnomad NFE AF: 0.651

Gnomad OTH AF: 0.569

GnomAD2 exomes AF: 0.602 AC: 151223 AN: 251296 AF XY: 0.605

Gnomad AFR exome AF: 0.279

Gnomad AMR exome AF: 0.622

Gnomad ASJ exome AF: 0.623

Gnomad EAS exome AF: 0.469

Gnomad FIN exome AF: 0.709

Gnomad NFE exome AF: 0.657

Gnomad OTH exome AF: 0.641

GnomAD4 exome AF: 0.631 AC: 920528 AN: 1457994 Hom.: 294576 Cov.: 59 AF XY: 0.630 AC XY: 457071 AN XY: 725372

African (AFR) AF: 0.271 AC: 9058 AN: 33366

American (AMR) AF: 0.623 AC: 27802 AN: 44620

Ashkenazi Jewish (ASJ) AF: 0.623 AC: 16183 AN: 25986

East Asian (EAS) AF: 0.557 AC: 22068 AN: 39636

South Asian (SAS) AF: 0.533 AC: 45904 AN: 86202

European-Finnish (FIN) AF: 0.706 AC: 37495 AN: 53098

Middle Eastern (MID) AF: 0.669 AC: 3843 AN: 5744

European-Non Finnish (NFE) AF: 0.651 AC: 721715 AN: 1109204

Other (OTH) AF: 0.606 AC: 36460 AN: 60138

GnomAD4 genome AF: 0.539 AC: 81951 AN: 151966 Hom.: 24159 Cov.: 34 AF XY: 0.543 AC XY: 40355 AN XY: 74256

African (AFR) AF: 0.285 AC: 11818 AN: 41470

American (AMR) AF: 0.610 AC: 9326 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.620 AC: 2149 AN: 3464

East Asian (EAS) AF: 0.485 AC: 2506 AN: 5162

South Asian (SAS) AF: 0.520 AC: 2507 AN: 4822

European-Finnish (FIN) AF: 0.714 AC: 7538 AN: 10556

Middle Eastern (MID) AF: 0.626 AC: 184 AN: 294

European-Non Finnish (NFE) AF: 0.651 AC: 44222 AN: 67898

Other (OTH) AF: 0.566 AC: 1193 AN: 2108

Alfa AF: 0.360 Hom.: 12200

Bravo AF: 0.524

TwinsUK AF: 0.646 AC: 2396

ALSPAC AF: 0.649 AC: 2503

ESP6500AA AF: 0.289 AC: 1271

ESP6500EA AF: 0.647 AC: 5567

ExAC AF: 0.596 AC: 72344

Asia WGS AF: 0.516 AC: 1796 AN: 3478

EpiCase AF: 0.658

EpiControl AF: 0.657

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	19
DANN	Benign	0.88
DEOGEN2	Benign	0.32	T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.34
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.73	T
MetaRNN	Benign	0.0000033	T
MetaSVM	Benign	-1.0	T
PhyloP100		1.2
PROVEAN	Uncertain	-4.2	D
REVEL	Benign	0.11
Sift	Uncertain	0.0080	D
Sift4G	Benign	0.11	T
Polyphen		0.93	P
Vest4		0.16
MPC		0.13
ClinPred		0.047	T
GERP RS		2.0
Varity_R		0.76
gMVP		0.21
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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

Other links and lift over

dbSNP: rs11640851; hg19: chr16-56673227; COSMIC: COSV51947373; COSMIC: COSV51947373;