16-56640199-C-G

Variant names:

• chr16-56640199-C-G
• rs904777
• NM_005946.3:c.*249C>G

Variant summary

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

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0320
• Publications: 8 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 (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.646 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MT1A	NM_005946.3	c.*249C>G		downstream_gene_variant		ENST00000290705.12	NP_005937.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MT1A	ENST00000290705.12	c.*249C>G		downstream_gene_variant		1	NM_005946.3	ENSP00000290705.8

Frequencies

GnomAD3 genomes AF: 0.541 AC: 82224 AN: 151912 Hom.: 24257 Cov.: 33

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

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

GnomAD4 genome AF: 0.541 AC: 82241 AN: 152032 Hom.: 24263 Cov.: 33 AF XY: 0.545 AC XY: 40534 AN XY: 74326

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

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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.3
DANN	Benign	0.57
PhyloP100		0.032
Mutation Taster		=95/5	polymorphism

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

Other links and lift over

dbSNP: rs904777; hg19: chr16-56674111;