16-56639337-T-C

Variant names:

• chr16-56639337-T-C
• rs11647171
• NM_005946.3:c.94+8T>C

Variant summary

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

The NM_005946.3(MT1A):​c.94+8T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.63 in 1,607,416 control chromosomes in the GnomAD database, including 322,787 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.58 (26235 hom., cov: 34)
  • Exomes 𝑓: 0.64 (296552 hom.)
• Consequence: MT1A NM_005946.3 splice_region, intron
• Scores: Splicing: ADA: 0.00001285
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.32
• Publications: 13 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=-0.82).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.647 is higher than 0.05.

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.94+8T>C		splice_region intron	N/A	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.94+8T>C		splice_region intron	N/A	ENSP00000290705.8	P04731
	MT1A	ENST00000908024.1		c.94+8T>C		splice_region intron	N/A	ENSP00000578083.1
	MT1A	ENST00000927706.1		c.55+8T>C		splice_region intron	N/A	ENSP00000597765.1

Frequencies

GnomAD3 genomes AF: 0.577 AC: 87671 AN: 151846 Hom.: 26228 Cov.: 34

Gnomad AFR AF: 0.418

Gnomad AMI AF: 0.560

Gnomad AMR AF: 0.623

Gnomad ASJ AF: 0.620

Gnomad EAS AF: 0.485

Gnomad SAS AF: 0.518

Gnomad FIN AF: 0.714

Gnomad MID AF: 0.639

Gnomad NFE AF: 0.652

Gnomad OTH AF: 0.588

GnomAD2 exomes AF: 0.611 AC: 153503 AN: 251066 AF XY: 0.612

Gnomad AFR exome AF: 0.415

Gnomad AMR exome AF: 0.628

Gnomad ASJ exome AF: 0.623

Gnomad EAS exome AF: 0.469

Gnomad FIN exome AF: 0.708

Gnomad NFE exome AF: 0.657

Gnomad OTH exome AF: 0.644

GnomAD4 exome AF: 0.635 AC: 924676 AN: 1455452 Hom.: 296552 Cov.: 53 AF XY: 0.634 AC XY: 458816 AN XY: 724252

African (AFR) AF: 0.410 AC: 13699 AN: 33378

American (AMR) AF: 0.630 AC: 28093 AN: 44602

Ashkenazi Jewish (ASJ) AF: 0.623 AC: 16167 AN: 25968

East Asian (EAS) AF: 0.557 AC: 22057 AN: 39614

South Asian (SAS) AF: 0.532 AC: 45837 AN: 86154

European-Finnish (FIN) AF: 0.706 AC: 37394 AN: 52952

Middle Eastern (MID) AF: 0.675 AC: 3865 AN: 5726

European-Non Finnish (NFE) AF: 0.651 AC: 720640 AN: 1107000

Other (OTH) AF: 0.615 AC: 36924 AN: 60058

GnomAD4 genome AF: 0.577 AC: 87699 AN: 151964 Hom.: 26235 Cov.: 34 AF XY: 0.580 AC XY: 43059 AN XY: 74264

African (AFR) AF: 0.417 AC: 17305 AN: 41470

American (AMR) AF: 0.623 AC: 9526 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.620 AC: 2151 AN: 3468

East Asian (EAS) AF: 0.485 AC: 2505 AN: 5160

South Asian (SAS) AF: 0.520 AC: 2506 AN: 4820

European-Finnish (FIN) AF: 0.714 AC: 7536 AN: 10554

Middle Eastern (MID) AF: 0.629 AC: 185 AN: 294

European-Non Finnish (NFE) AF: 0.652 AC: 44248 AN: 67904

Other (OTH) AF: 0.585 AC: 1233 AN: 2108

Alfa AF: 0.611 Hom.: 7652

Bravo AF: 0.567

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.14
DANN	Benign	0.51
PhyloP100		-2.3
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000013
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.010		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: rs11647171; hg19: chr16-56673249; COSMIC: COSV51947550; COSMIC: COSV51947550;