16-56567808-A-G

Position:

• chr16-56567808-A-G

Variant summary

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

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. 11/19 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 nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.91 (63908 hom., cov: 30)
  • Exomes 𝑓: 0.96 (674946 hom.)
• Consequence: MT4 NM_032935.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.02

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]

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]

ACMG classification

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MT4	NM_032935.3	c.89A>G	p.Tyr30Cys	missense_variant	2/3	ENST00000219162.4	NP_116324.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MT4	ENST00000219162.4	c.89A>G	p.Tyr30Cys	missense_variant	2/3	1	NM_032935.3	ENSP00000219162.3
BBS2	ENST00000682930.1	c.42+2867T>C		intron_variant				ENSP00000507981.1

Frequencies

GnomAD3 genomes AF: 0.914 AC: 138679 AN: 151722 Hom.: 63881 Cov.: 30

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

GnomAD3 exomes AF: 0.936 AC: 233501 AN: 249478 Hom.: 110036 AF XY: 0.941 AC XY: 127416 AN XY: 135346

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 SAS exome AF: 0.958

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.: 36 AF XY: 0.961 AC XY: 698055 AN XY: 726524

Gnomad4 AFR exome AF: 0.796

Gnomad4 AMR exome AF: 0.949

Gnomad4 ASJ exome AF: 0.950

Gnomad4 EAS exome AF: 0.725

Gnomad4 SAS exome AF: 0.958

Gnomad4 FIN exome AF: 0.958

Gnomad4 NFE exome AF: 0.975

Gnomad4 OTH exome AF: 0.947

GnomAD4 genome AF: 0.914 AC: 138760 AN: 151840 Hom.: 63908 Cov.: 30 AF XY: 0.912 AC XY: 67691 AN XY: 74216

Gnomad4 AFR AF: 0.803

Gnomad4 AMR AF: 0.951

Gnomad4 ASJ AF: 0.953

Gnomad4 EAS AF: 0.717

Gnomad4 SAS AF: 0.951

Gnomad4 FIN AF: 0.958

Gnomad4 NFE AF: 0.975

Gnomad4 OTH AF: 0.923

Alfa AF: 0.959 Hom.: 171777

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 v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.052
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	16
DANN	Benign	0.82
DEOGEN2	Benign	0.057	T
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.29
FATHMM_MKL	Benign	0.019	N
LIST_S2	Benign	0.46	T
MetaRNN	Benign	0.0000010	T
MetaSVM	Benign	-0.94	T
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	9.2	N
REVEL	Benign	0.18
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.090
MPC		0.019
ClinPred		0.0037	T
GERP RS		5.7
Varity_R		0.057
gMVP		0.29

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: rs666636; hg19: chr16-56601720;