16-56567810-T-C

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.91T>C(p.Trp31Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.957 in 1,612,060 control chromosomes in the GnomAD database, including 740,788 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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 0.92 ( 64966 hom., cov: 30)

Exomes 𝑓: 0.96 ( 675822 hom. )

Consequence

MT4
NM_032935.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.436

Publications

22 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: Ambry Genetics, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Myriad Women’s Health
BBS2-related 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=5.3134695E-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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MT4	NM_032935.3	MANE Select	c.91T>C	p.Trp31Arg	missense	Exon 2 of 3	NP_116324.2	P47944

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MT4	ENST00000219162.4	TSL:1 MANE Select	c.91T>C	p.Trp31Arg	missense	Exon 2 of 3	ENSP00000219162.3	P47944
	BBS2	ENST00000682930.1		c.42+2865A>G		intron	N/A	ENSP00000507981.1	A0A804HKL9

Frequencies

GnomAD3 genomes

AF:

0.923

AC:

139957

AN:

151696

Hom.:

64935

Cov.:

show subpopulations

Gnomad AFR

AF:

0.833

Gnomad AMI

AF:

0.966

Gnomad AMR

AF:

0.954

Gnomad ASJ

AF:

0.953

Gnomad EAS

AF:

0.716

Gnomad SAS

AF:

0.952

Gnomad FIN

AF:

0.958

Gnomad MID

AF:

0.972

Gnomad NFE

AF:

0.975

Gnomad OTH

AF:

0.934

GnomAD2 exomes

AF:

0.938

AC:

234001

AN:

249484

AF XY:

0.943

show subpopulations

Gnomad AFR exome

AF:

0.823

Gnomad AMR exome

AF:

0.951

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:

0.950

GnomAD4 exome

AF:

0.961

AC:

1403133

AN:

1460246

Hom.:

675822

Cov.:

AF XY:

0.961

AC XY:

698427

AN XY:

726428

show subpopulations

African (AFR)

AF:

0.825

AC:

27572

AN:

33422

American (AMR)

AF:

0.950

AC:

42453

AN:

44670

Ashkenazi Jewish (ASJ)

AF:

0.950

AC:

24787

AN:

26098

East Asian (EAS)

AF:

0.725

AC:

28741

AN:

39646

South Asian (SAS)

AF:

0.958

AC:

82576

AN:

86218

European-Finnish (FIN)

AF:

0.958

AC:

51031

AN:

53292

Middle Eastern (MID)

AF:

0.968

AC:

5576

AN:

5760

European-Non Finnish (NFE)

AF:

0.975

AC:

1083223

AN:

1110848

Other (OTH)

AF:

0.948

AC:

57174

AN:

60292

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

2380

4760

7140

9520

11900

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:

0.922

AC:

140042

AN:

151814

Hom.:

64966

Cov.:

AF XY:

0.920

AC XY:

68301

AN XY:

74210

show subpopulations

African (AFR)

AF:

0.833

AC:

34454

AN:

41338

American (AMR)

AF:

0.954

AC:

14563

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.953

AC:

3308

AN:

3470

East Asian (EAS)

AF:

0.716

AC:

3658

AN:

5108

South Asian (SAS)

AF:

0.952

AC:

4581

AN:

4814

European-Finnish (FIN)

AF:

0.958

AC:

10124

AN:

10568

Middle Eastern (MID)

AF:

0.969

AC:

285

AN:

294

European-Non Finnish (NFE)

AF:

0.975

AC:

66234

AN:

67938

Other (OTH)

AF:

0.930

AC:

1956

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

496

992

1488

1984

2480

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

900

1800

2700

3600

4500

<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:

0.955

Hom.:

298077

Bravo

AF:

0.916

TwinsUK

AF:

0.979

AC:

3631

ALSPAC

AF:

0.973

AC:

3749

ESP6500AA

AF:

0.836

AC:

3375

ESP6500EA

AF:

0.976

AC:

8176

ExAC

AF:

0.937

AC:

113287

Asia WGS

AF:

0.851

AC:

2961

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

-0.73

BayesDel_noAF

Benign

-0.68

CADD

Benign

(source)

DANN

Benign

0.68

DEOGEN2

Benign

0.069

Eigen

Benign

-0.68

Eigen_PC

Benign

-0.58

FATHMM_MKL

Benign

0.0077

LIST_S2

Benign

0.049

MetaRNN

Benign

0.0000053

MetaSVM

Benign

-0.95

PhyloP100

0.44

PrimateAI

Benign

0.27

PROVEAN

Benign

4.7

REVEL

Benign

0.079

Sift

Benign

0.85

Sift4G

Benign

0.32

Polyphen

0.0

Vest4

0.044

MutPred

0.29

Loss of ubiquitination at K28 (P = 0.0367)

MPC

0.021

ClinPred

0.0025

GERP RS

4.7

Varity_R

0.046

gMVP

0.092

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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