16-56639315-C-G

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005946.3(MT1A):​c.80C>G​(p.Thr27Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
  • Failed GnomAD Quality Control
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20622486).

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.80C>G	p.Thr27Ser	missense	Exon 2 of 3	NP_005937.2	P04731

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MT1A	ENST00000290705.12	TSL:1 MANE Select	c.80C>G	p.Thr27Ser	missense	Exon 2 of 3	ENSP00000290705.8	P04731
	MT1A	ENST00000908024.1		c.80C>G	p.Thr27Ser	missense	Exon 3 of 4	ENSP00000578083.1
	MT1A	ENST00000927706.1		c.41C>G	p.Thr14Ser	missense	Exon 2 of 3	ENSP00000597765.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 6.85e-7 AC: 1 AN: 1459552 Hom.: 0 Cov.: 59 AF XY: 0.00 AC XY: 0 AN XY: 726074

African (AFR) AF: 0.00 AC: 0 AN: 33448

American (AMR) AF: 0.00 AC: 0 AN: 44640

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26010

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39650

South Asian (SAS) AF: 0.00 AC: 0 AN: 86238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53156

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110444

Other (OTH) AF: 0.00 AC: 0 AN: 60212

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	19
DANN	Benign	0.75
DEOGEN2	Benign	0.32	T
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.47
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.59	T
M_CAP	Benign	0.0039	T
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-1.1	T
PhyloP100		1.2
PROVEAN	Uncertain	-3.2	D
REVEL	Benign	0.079
Sift	Uncertain	0.022	D
Sift4G	Benign	0.28	T
Polyphen		0.64	P
Vest4		0.24
MutPred		0.29		Loss of sheet (P = 0.0817)
MVP		0.20
MPC		0.099
ClinPred		0.87	D
GERP RS		2.0
Varity_R		0.34
gMVP		0.089

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: rs11640851; hg19: chr16-56673227; COSMIC: COSV51947417; COSMIC: COSV51947417;