16-56670526-G-A

Variant names:

• chr16-56670526-G-A
• rs9934181
• NM_005951.2:c.49G>A

Variant summary

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

The NM_005951.2(MT1H):​c.49G>A​(p.Gly17Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00588 in 1,614,198 control chromosomes in the GnomAD database, including 382 homozygotes. 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G17V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.028 (183 hom., cov: 33)
  • Exomes 𝑓: 0.0036 (199 hom.)
• Consequence: MT1H NM_005951.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0160
• Publications: 5 publications found

Genes affected

MT1H (HGNC:7400): (metallothionein 1H) Predicted to enable zinc ion binding activity. Involved in cellular response to cadmium ion and cellular response to zinc ion. Predicted to be active in cytoplasm and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0021295547).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0927 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005951.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MT1H	NM_005951.2	MANE Select	c.49G>A	p.Gly17Ser	missense	Exon 2 of 3	NP_005942.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MT1H	ENST00000332374.5	TSL:1 MANE Select	c.49G>A	p.Gly17Ser	missense	Exon 2 of 3	ENSP00000330587.5
	MT1H	ENST00000569155.1	TSL:1	c.49G>A	p.Gly17Ser	missense	Exon 2 of 2	ENSP00000457114.1

Frequencies

GnomAD3 genomes AF: 0.0279 AC: 4247 AN: 152204 Hom.: 183 Cov.: 33

Gnomad AFR AF: 0.0952

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00870

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00311

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00154

Gnomad OTH AF: 0.0220

GnomAD2 exomes AF: 0.00781 AC: 1964 AN: 251428 AF XY: 0.00594

Gnomad AFR exome AF: 0.0973

Gnomad AMR exome AF: 0.00526

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00120

Gnomad OTH exome AF: 0.00424

GnomAD4 exome AF: 0.00358 AC: 5235 AN: 1461876 Hom.: 199 Cov.: 32 AF XY: 0.00323 AC XY: 2349 AN XY: 727236

African (AFR) AF: 0.101 AC: 3382 AN: 33480

American (AMR) AF: 0.00539 AC: 241 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000191 AC: 5 AN: 26134

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.00148 AC: 128 AN: 86258

European-Finnish (FIN) AF: 0.0000374 AC: 2 AN: 53418

Middle Eastern (MID) AF: 0.00902 AC: 52 AN: 5768

European-Non Finnish (NFE) AF: 0.000973 AC: 1082 AN: 1111998

Other (OTH) AF: 0.00565 AC: 341 AN: 60396

GnomAD4 genome AF: 0.0279 AC: 4256 AN: 152322 Hom.: 183 Cov.: 33 AF XY: 0.0268 AC XY: 1996 AN XY: 74492

African (AFR) AF: 0.0952 AC: 3956 AN: 41560

American (AMR) AF: 0.00869 AC: 133 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00270 AC: 13 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00154 AC: 105 AN: 68028

Other (OTH) AF: 0.0217 AC: 46 AN: 2116

Alfa AF: 0.0140 Hom.: 74

Bravo AF: 0.0315

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.0939 AC: 413

ESP6500EA AF: 0.00209 AC: 18

ExAC AF: 0.00949 AC: 1152

Asia WGS AF: 0.00635 AC: 22 AN: 3478

EpiCase AF: 0.00229

EpiControl AF: 0.00154

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	1.7
DANN	Benign	0.62
DEOGEN2	Benign	0.082	T
Eigen	Benign	-0.95
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.046	N
LIST_S2	Benign	0.27	T
MetaRNN	Benign	0.0021	T
MetaSVM	Benign	-0.91	T
PhyloP100		0.016
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.35	N
REVEL	Benign	0.027
Sift	Benign	0.47	T
Sift4G	Benign	0.50	T
Polyphen		0.029	B
Vest4		0.25
MVP		0.014
MPC		0.013
ClinPred		0.00085	T
GERP RS		1.5
Varity_R		0.029
gMVP		0.065
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs9934181; hg19: chr16-56704438; COSMIC: COSV60090987; COSMIC: COSV60090987;