16-56633370-C-A

Variant names:

• chr16-56633370-C-A
• rs1827210
• NM_176870.3:c.59C>A

Variant summary

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

The NM_176870.3(MT1M):​c.59C>A​(p.Thr20Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.832 in 1,614,012 control chromosomes in the GnomAD database, including 562,517 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T20R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.77 (45971 hom., cov: 34)
  • Exomes 𝑓: 0.84 (516546 hom.)
• Consequence: MT1M NM_176870.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.207
• Publications: 28 publications found

Genes affected

MT1M (HGNC:14296): (metallothionein 1M) This gene encodes a member of the metallothionein superfamily, type 1 family. Metallothioneins have a high content of cysteine residues that bind various heavy metals. These genes are transcriptionally regulated by both heavy metals and glucocorticoids. [provided by RefSeq, Oct 2011]

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=9.826878E-7).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.851 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_176870.3. 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
	MT1M	NM_176870.3	MANE Select	c.59C>A	p.Thr20Lys	missense	Exon 2 of 3	NP_789846.2	Q8N339

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MT1M	ENST00000379818.4	TSL:1 MANE Select	c.59C>A	p.Thr20Lys	missense	Exon 2 of 3	ENSP00000369146.3	Q8N339
	MT1M	ENST00000570233.1	TSL:3	c.59C>A	p.Thr20Lys	missense	Exon 2 of 2	ENSP00000457575.1	H3BUC6
	MT1M	ENST00000858452.1		c.29-381C>A		intron	N/A	ENSP00000528511.1

Frequencies

GnomAD3 genomes AF: 0.769 AC: 116959 AN: 152044 Hom.: 45962 Cov.: 34

Gnomad AFR AF: 0.595

Gnomad AMI AF: 0.730

Gnomad AMR AF: 0.808

Gnomad ASJ AF: 0.808

Gnomad EAS AF: 0.669

Gnomad SAS AF: 0.795

Gnomad FIN AF: 0.853

Gnomad MID AF: 0.839

Gnomad NFE AF: 0.857

Gnomad OTH AF: 0.788

GnomAD2 exomes AF: 0.808 AC: 202987 AN: 251280 AF XY: 0.815

Gnomad AFR exome AF: 0.590

Gnomad AMR exome AF: 0.784

Gnomad ASJ exome AF: 0.803

Gnomad EAS exome AF: 0.661

Gnomad FIN exome AF: 0.860

Gnomad NFE exome AF: 0.856

Gnomad OTH exome AF: 0.831

GnomAD4 exome AF: 0.839 AC: 1226355 AN: 1461850 Hom.: 516546 Cov.: 117 AF XY: 0.839 AC XY: 610393 AN XY: 727232

African (AFR) AF: 0.587 AC: 19637 AN: 33474

American (AMR) AF: 0.790 AC: 35351 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.798 AC: 20850 AN: 26134

East Asian (EAS) AF: 0.708 AC: 28096 AN: 39698

South Asian (SAS) AF: 0.814 AC: 70215 AN: 86258

European-Finnish (FIN) AF: 0.857 AC: 45806 AN: 53420

Middle Eastern (MID) AF: 0.862 AC: 4970 AN: 5768

European-Non Finnish (NFE) AF: 0.856 AC: 952353 AN: 1111992

Other (OTH) AF: 0.813 AC: 49077 AN: 60386

GnomAD4 genome AF: 0.769 AC: 117003 AN: 152162 Hom.: 45971 Cov.: 34 AF XY: 0.769 AC XY: 57178 AN XY: 74380

African (AFR) AF: 0.595 AC: 24667 AN: 41474

American (AMR) AF: 0.808 AC: 12348 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.808 AC: 2804 AN: 3472

East Asian (EAS) AF: 0.670 AC: 3446 AN: 5146

South Asian (SAS) AF: 0.797 AC: 3850 AN: 4830

European-Finnish (FIN) AF: 0.853 AC: 9056 AN: 10612

Middle Eastern (MID) AF: 0.847 AC: 249 AN: 294

European-Non Finnish (NFE) AF: 0.857 AC: 58261 AN: 68018

Other (OTH) AF: 0.783 AC: 1656 AN: 2114

Alfa AF: 0.808 Hom.: 18473

Bravo AF: 0.758

ESP6500AA AF: 0.602 AC: 2646

ESP6500EA AF: 0.851 AC: 7317

ExAC AF: 0.806 AC: 97904

Asia WGS AF: 0.732 AC: 2548 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.053
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	0.50
DANN	Benign	0.77
DEOGEN2	Benign	0.071	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.015	N
LIST_S2	Benign	0.029	T
MetaRNN	Benign	9.8e-7	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.21
PrimateAI	Benign	0.28	T
PROVEAN	Benign	4.0	N
REVEL	Benign	0.019
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.061
MPC		0.012
ClinPred		0.00022	T
GERP RS		-0.081
Varity_R		0.047
gMVP		0.033
Mutation Taster		=99/1	polymorphism (auto)

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: rs1827210; hg19: chr16-56667282; COSMIC: COSV65835940; COSMIC: COSV65835940;