chr16-56568895-G-A
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Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate
The NM_032935.3(MT4):c.152G>A(p.Cys51Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.0000958 in 1,608,076 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00010 ( 0 hom. )
Consequence
MT4
NM_032935.3 missense
NM_032935.3 missense
Scores
6
6
6
Clinical Significance
Conservation
PhyloP100: 6.09
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PM1
In a binding_site (size 0) in uniprot entity MT4_HUMAN
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.864
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MT4 | NM_032935.3 | c.152G>A | p.Cys51Tyr | missense_variant | 3/3 | ENST00000219162.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MT4 | ENST00000219162.4 | c.152G>A | p.Cys51Tyr | missense_variant | 3/3 | 1 | NM_032935.3 | P1 | |
BBS2 | ENST00000682930.1 | c.42+1780C>T | intron_variant |
Frequencies
GnomAD3 genomes AF: 0.0000329 AC: 5AN: 152192Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000326 AC: 8AN: 245116Hom.: 0 AF XY: 0.0000301 AC XY: 4AN XY: 132910
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GnomAD4 exome AF: 0.000102 AC: 149AN: 1455884Hom.: 0 Cov.: 31 AF XY: 0.000106 AC XY: 77AN XY: 724282
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GnomAD4 genome AF: 0.0000329 AC: 5AN: 152192Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74344
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 01, 2022 | The c.152G>A (p.C51Y) alteration is located in exon 3 (coding exon 3) of the MT4 gene. This alteration results from a G to A substitution at nucleotide position 152, causing the cysteine (C) at amino acid position 51 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
T
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T
M_CAP
Benign
D
MetaRNN
Pathogenic
D
MetaSVM
Benign
T
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D
REVEL
Uncertain
Sift
Pathogenic
D
Sift4G
Pathogenic
D
Polyphen
D
Vest4
MVP
MPC
ClinPred
D
GERP RS
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gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at