rs8052394

Positions:

• chr16-56639916-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000290705.12(MT1A):​c.152A>G​(p.Lys51Arg) variant causes a missense change. The variant allele was found at a frequency of 0.133 in 1,613,782 control chromosomes in the GnomAD database, including 14,835 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. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.15 (1641 hom., cov: 33)
  • Exomes 𝑓: 0.13 (13194 hom.)
• Consequence: MT1A ENST00000290705.12 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.37

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

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0023518503).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.22 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MT1A	NM_005946.3	c.152A>G	p.Lys51Arg	missense_variant	3/3	ENST00000290705.12	NP_005937.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MT1A	ENST00000290705.12	c.152A>G	p.Lys51Arg	missense_variant	3/3	1	NM_005946.3	ENSP00000290705	P1

Frequencies

GnomAD3 genomes AF: 0.146 AC: 22138 AN: 152134 Hom.: 1637 Cov.: 33

Gnomad AFR AF: 0.168

Gnomad AMI AF: 0.264

Gnomad AMR AF: 0.144

Gnomad ASJ AF: 0.184

Gnomad EAS AF: 0.231

Gnomad SAS AF: 0.178

Gnomad FIN AF: 0.127

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.123

Gnomad OTH AF: 0.139

GnomAD3 exomes AF: 0.148 AC: 37114 AN: 251410 Hom.: 2830 AF XY: 0.146 AC XY: 19848 AN XY: 135866

Gnomad AFR exome AF: 0.165

Gnomad AMR exome AF: 0.167

Gnomad ASJ exome AF: 0.188

Gnomad EAS exome AF: 0.236

Gnomad SAS exome AF: 0.160

Gnomad FIN exome AF: 0.118

Gnomad NFE exome AF: 0.124

Gnomad OTH exome AF: 0.136

GnomAD4 exome AF: 0.132 AC: 192508 AN: 1461532 Hom.: 13194 Cov.: 32 AF XY: 0.132 AC XY: 96234 AN XY: 727080

Gnomad4 AFR exome AF: 0.165

Gnomad4 AMR exome AF: 0.162

Gnomad4 ASJ exome AF: 0.192

Gnomad4 EAS exome AF: 0.217

Gnomad4 SAS exome AF: 0.163

Gnomad4 FIN exome AF: 0.119

Gnomad4 NFE exome AF: 0.122

Gnomad4 OTH exome AF: 0.146

GnomAD4 genome AF: 0.145 AC: 22152 AN: 152250 Hom.: 1641 Cov.: 33 AF XY: 0.148 AC XY: 11010 AN XY: 74458

Gnomad4 AFR AF: 0.167

Gnomad4 AMR AF: 0.144

Gnomad4 ASJ AF: 0.184

Gnomad4 EAS AF: 0.231

Gnomad4 SAS AF: 0.176

Gnomad4 FIN AF: 0.127

Gnomad4 NFE AF: 0.123

Gnomad4 OTH AF: 0.144

Alfa AF: 0.134 Hom.: 593

Bravo AF: 0.147

ESP6500AA AF: 0.174 AC: 764

ESP6500EA AF: 0.129 AC: 1108

ExAC AF: 0.147 AC: 17800

Asia WGS AF: 0.198 AC: 688 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Benign	0.29	T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.53
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.73	T
MetaRNN	Benign	0.0024	T
MetaSVM	Benign	-0.99	T
MutationTaster	Benign	0.55	P
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.12
Sift	Uncertain	0.015	D
Sift4G	Uncertain	0.039	D
Polyphen		0.11	B
Vest4		0.21
MPC		0.090
ClinPred		0.026	T
GERP RS		1.9
Varity_R		0.30
gMVP		0.36

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

Other links and lift over

dbSNP: rs8052394; hg19: chr16-56673828; COSMIC: COSV51947452; COSMIC: COSV51947452;