16-56567808-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_032935.3(MT4):c.89A>G(p.Tyr30Cys) variant causes a missense change. The variant allele was found at a frequency of 0.956 in 1,612,280 control chromosomes in the GnomAD database, including 738,854 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 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 0.91 ( 63908 hom., cov: 30)

Exomes 𝑓: 0.96 ( 674946 hom. )

Consequence

MT4
NM_032935.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.02

Publications

23 publications found

Variant links:

Genes affected

MT4 (HGNC:18705): (metallothionein 4) Predicted to enable metal ion binding activity. Predicted to be involved in cellular response to metal ion; cellular zinc ion homeostasis; and detoxification of copper ion. Predicted to act upstream of or within cellular metal ion homeostasis. Predicted to be active in cytoplasm and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

MT4 links:

BBS2 (HGNC:967): (Bardet-Biedl syndrome 2) This gene is a member of the Bardet-Biedl syndrome (BBS) gene family. Bardet-Biedl syndrome is an autosomal recessive disorder characterized by severe pigmentary retinopathy, obesity, polydactyly, renal malformation and cognitive disability. The proteins encoded by BBS gene family members are structurally diverse and the similar phenotypes exhibited by mutations in BBS gene family members is likely due to their shared roles in cilia formation and function. Many BBS proteins localize to the basal bodies, ciliary axonemes, and pericentriolar regions of cells. BBS proteins may also be involved in intracellular trafficking via microtubule-related transport. The protein encoded by this gene forms a multiprotein BBSome complex with seven other BBS proteins.[provided by RefSeq, Oct 2014]

BBS2 Gene-Disease associations (from GenCC):

Bardet-Biedl syndrome 2
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Myriad Women’s Health
ciliopathy
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
retinitis pigmentosa 74
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
retinitis pigmentosa
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Bardet-Biedl syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

BBS2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=1.0253634E-6).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.969 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032935.3. 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
	MT4	NM_032935.3	MANE Select	c.89A>G	p.Tyr30Cys	missense	Exon 2 of 3	NP_116324.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MT4	ENST00000219162.4	TSL:1 MANE Select	c.89A>G	p.Tyr30Cys	missense	Exon 2 of 3	ENSP00000219162.3
	BBS2	ENST00000682930.1		c.42+2867T>C		intron	N/A	ENSP00000507981.1

Frequencies

GnomAD3 genomes

AF:

0.914

AC:

138679

AN:

151722

Hom.:

63881

Cov.:

show subpopulations

Gnomad AFR

AF:

0.803

Gnomad AMI

AF:

0.966

Gnomad AMR

AF:

0.951

Gnomad ASJ

AF:

0.953

Gnomad EAS

AF:

0.717

Gnomad SAS

AF:

0.951

Gnomad FIN

AF:

0.958

Gnomad MID

AF:

0.972

Gnomad NFE

AF:

0.975

Gnomad OTH

AF:

0.927

GnomAD2 exomes

AF:

0.936

AC:

233501

AN:

249478

AF XY:

0.941

show subpopulations

Gnomad AFR exome

AF:

0.794

Gnomad AMR exome

AF:

0.950

Gnomad ASJ exome

AF:

0.950

Gnomad EAS exome

AF:

0.713

Gnomad FIN exome

AF:

0.957

Gnomad NFE exome

AF:

0.975

Gnomad OTH exome

AF:

0.948

GnomAD4 exome

AF:

0.960

AC:

1402165

AN:

1460440

Hom.:

674946

Cov.:

AF XY:

0.961

AC XY:

698055

AN XY:

726524

show subpopulations

African (AFR)

AF:

0.796

AC:

26596

AN:

33430

American (AMR)

AF:

0.949

AC:

42398

AN:

44678

Ashkenazi Jewish (ASJ)

AF:

0.950

AC:

24787

AN:

26098

East Asian (EAS)

AF:

0.725

AC:

28756

AN:

39652

South Asian (SAS)

AF:

0.958

AC:

82571

AN:

86218

European-Finnish (FIN)

AF:

0.958

AC:

51049

AN:

53310

Middle Eastern (MID)

AF:

0.967

AC:

5572

AN:

5764

European-Non Finnish (NFE)

AF:

0.975

AC:

1083339

AN:

1110990

Other (OTH)

AF:

0.947

AC:

57097

AN:

60300

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

2422

4844

7266

9688

12110

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21608

43216

64824

86432

108040

<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:

0.914

AC:

138760

AN:

151840

Hom.:

63908

Cov.:

AF XY:

0.912

AC XY:

67691

AN XY:

74216

show subpopulations

African (AFR)

AF:

0.803

AC:

33222

AN:

41356

American (AMR)

AF:

0.951

AC:

14518

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.953

AC:

3308

AN:

3470

East Asian (EAS)

AF:

0.717

AC:

3661

AN:

5108

South Asian (SAS)

AF:

0.951

AC:

4585

AN:

4820

European-Finnish (FIN)

AF:

0.958

AC:

10131

AN:

10576

Middle Eastern (MID)

AF:

0.969

AC:

285

AN:

294

European-Non Finnish (NFE)

AF:

0.975

AC:

66228

AN:

67934

Other (OTH)

AF:

0.923

AC:

1943

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

548

1096

1643

2191

2739

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

898

1796

2694

3592

4490

<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:

0.953

Hom.:

312424

Bravo

AF:

0.907

TwinsUK

AF:

0.979

AC:

3631

ALSPAC

AF:

0.972

AC:

3748

ESP6500AA

AF:

0.809

AC:

3278

ESP6500EA

AF:

0.976

AC:

8192

ExAC

AF:

0.935

AC:

112997

Asia WGS

AF:

0.849

AC:

2954

AN:

3478

EpiCase

AF:

0.975

EpiControl

AF:

0.976

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.052

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.53

CADD

Benign

(source)

DANN

Benign

0.82

DEOGEN2

Benign

0.057

Eigen

Benign

-0.46

Eigen_PC

Benign

-0.29

FATHMM_MKL

Benign

0.019

LIST_S2

Benign

0.46

MetaRNN

Benign

0.0000010

MetaSVM

Benign

-0.94

PhyloP100

4.0

PrimateAI

Uncertain

0.51

PROVEAN

Benign

9.2

REVEL

Benign

0.18

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.090

MPC

0.019

ClinPred

0.0037

GERP RS

5.7

Varity_R

0.057

gMVP

0.29

Mutation Taster

=79/21

polymorphism (auto)

(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

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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