Genetic Variant MT1B:p.Cys19Ser (chr16-56652598-G-C) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 2P and 8B. PM1BP4_StrongBS2

The NM_005947.3(MT1B):c.56G>C(p.Cys19Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0055 in 1,613,984 control chromosomes in the GnomAD database, including 43 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.

Frequency

Genomes: 𝑓 0.0063 ( 6 hom., cov: 33)

Exomes 𝑓: 0.0054 ( 37 hom. )

Consequence

MT1B
NM_005947.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.56

Publications

8 publications found

Variant links:

Genes affected

MT1B (HGNC:7394): (metallothionein 1B) The protein encoded by this gene binds heavy metals and protects against toxicity from heavy metal ions. This gene is found in a cluster of similar genes on chromosome 16. [provided by RefSeq, Jul 2016]

MT1B links:

ENSG00000259923 (HGNC:):

ENSG00000259923 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

PM1

In a binding_site (size 0) in uniprot entity MT1B_HUMAN

BP4

Computational evidence support a benign effect (MetaRNN=0.007817745).

BS2

High Homozygotes in GnomAd4 at 6 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005947.3. 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
	MT1B	NM_005947.3	MANE Select	c.56G>C	p.Cys19Ser	missense	Exon 2 of 3	NP_005938.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MT1B	ENST00000334346.3	TSL:1 MANE Select	c.56G>C	p.Cys19Ser	missense	Exon 2 of 3	ENSP00000334998.2
MT1B	ENST00000562399.1	TSL:3	c.56G>C	p.Cys19Ser	missense	Exon 2 of 3	ENSP00000456056.1
ENSG00000259923	ENST00000568608.1	TSL:5	n.206G>C		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes

AF:

0.00627

AC:

954

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0102

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00504

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00414

Gnomad FIN

AF:

0.00593

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00514

Gnomad OTH

AF:

0.00430

GnomAD2 exomes

AF:

0.00463

AC:

1165

AN:

251486

AF XY:

0.00471

show subpopulations

Gnomad AFR exome

AF:

0.00960

Gnomad AMR exome

AF:

0.00341

Gnomad ASJ exome

AF:

0.00139

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00610

Gnomad NFE exome

AF:

0.00518

Gnomad OTH exome

AF:

0.00489

GnomAD4 exome

AF:

0.00542

AC:

7926

AN:

1461670

Hom.:

Cov.:

AF XY:

0.00539

AC XY:

3918

AN XY:

727136

show subpopulations

African (AFR)

AF:

0.00902

AC:

302

AN:

33472

American (AMR)

AF:

0.00391

AC:

175

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00130

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00435

AC:

375

AN:

86258

European-Finnish (FIN)

AF:

0.00674

AC:

360

AN:

53380

Middle Eastern (MID)

AF:

0.00815

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00567

AC:

6301

AN:

1111870

Other (OTH)

AF:

0.00550

AC:

332

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

392

784

1177

1569

1961

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

246

492

738

984

1230

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00627

AC:

955

AN:

152314

Hom.:

Cov.:

AF XY:

0.00623

AC XY:

464

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.0102

AC:

424

AN:

41576

American (AMR)

AF:

0.00503

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00173

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5180

South Asian (SAS)

AF:

0.00414

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00593

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.0137

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00515

AC:

350

AN:

68024

Other (OTH)

AF:

0.00426

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

106

158

211

264

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00502

Hom.:

Bravo

AF:

0.00632

TwinsUK

AF:

0.00593

AC:

ALSPAC

AF:

0.00389

AC:

ESP6500AA

AF:

0.00569

AC:

ESP6500EA

AF:

0.00477

AC:

ExAC

AF:

0.00446

AC:

541

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.00540

EpiControl

AF:

0.00456

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.31

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.28

CADD

Benign

(source)

DANN

Benign

0.69

DEOGEN2

Benign

0.36

Eigen

Benign

0.16

Eigen_PC

Benign

0.0047

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.61

MetaRNN

Benign

0.0078

MetaSVM

Benign

-0.75

PhyloP100

1.6

PrimateAI

Benign

0.34

PROVEAN

Pathogenic

-9.3

REVEL

Benign

0.27

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.019

Polyphen

0.97

Vest4

0.49

MutPred

0.69

Gain of relative solvent accessibility (P = 0.0166)

MVP

0.055

MPC

0.46

ClinPred

0.13

GERP RS

2.6

Varity_R

0.69

gMVP

0.46

Mutation Taster

=100/0

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over