16-56670526-G-A

Position:

• chr16-56670526-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000332374.5(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. 12/19 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 ENST00000332374.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0160

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

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MT1H	NM_005951.2	c.49G>A	p.Gly17Ser	missense_variant	2/3	ENST00000332374.5	NP_005942.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MT1H	ENST00000332374.5	c.49G>A	p.Gly17Ser	missense_variant	2/3	1	NM_005951.2	ENSP00000330587	P1
MT1H	ENST00000569155.1	c.49G>A	p.Gly17Ser	missense_variant	2/2	1		ENSP00000457114

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

GnomAD3 exomes AF: 0.00781 AC: 1964 AN: 251428 Hom.: 85 AF XY: 0.00594 AC XY: 807 AN XY: 135908

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 SAS exome AF: 0.00118

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

Gnomad4 AFR exome AF: 0.101

Gnomad4 AMR exome AF: 0.00539

Gnomad4 ASJ exome AF: 0.000191

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00148

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.000973

Gnomad4 OTH exome AF: 0.00565

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

Gnomad4 AFR AF: 0.0952

Gnomad4 AMR AF: 0.00869

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00270

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00154

Gnomad4 OTH AF: 0.0217

Alfa AF: 0.00635 Hom.: 12

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 v4.3

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;T
MetaRNN	Benign	0.0021	T;T
MetaSVM	Benign	-0.91	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.35	N;D
REVEL	Benign	0.027
Sift	Benign	0.47	T;T
Sift4G	Benign	0.50	T;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

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

Publications

LitVar

Other links and lift over

dbSNP: rs9934181; hg19: chr16-56704438; COSMIC: COSV60090987; COSMIC: COSV60090987;