chr16-56639871-G-A

Position:

• chr16-56639871-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_005946.3(MT1A):​c.107G>A​(p.Cys36Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: MT1A NM_005946.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.16

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 Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a binding_site (size 0) in uniprot entity MT1A_HUMAN
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MT1A	NM_005946.3	c.107G>A	p.Cys36Tyr	missense_variant	3/3	ENST00000290705.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MT1A	ENST00000290705.12	c.107G>A	p.Cys36Tyr	missense_variant	3/3	1	NM_005946.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 06, 2022

The c.107G>A (p.C36Y) alteration is located in exon 3 (coding exon 3) of the MT1A gene. This alteration results from a G to A substitution at nucleotide position 107, causing the cysteine (C) at amino acid position 36 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Benign	0.28	T
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.76	D
LIST_S2	Benign	0.85	D
M_CAP	Benign	0.0088	T
MetaRNN	Uncertain	0.61	D
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D
PROVEAN	Pathogenic	-8.9	D
REVEL	Benign	0.20
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.16	B
Vest4		0.63
MutPred		0.77		Loss of sheet (P = 0.1907);
MVP		0.23
MPC		0.71
ClinPred		1.0	D
GERP RS		2.1
Varity_R		0.91
gMVP		0.60

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-56673783;