rs267606657
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PP2PP3_StrongPP5
The NM_054027.6(ANKH):āc.1001T>Gā(p.Leu334Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,590 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 Pathogenic (no stars).
Frequency
Genomes: not found (cov: 33)
Exomes š: 6.8e-7 ( 0 hom. )
Consequence
ANKH
NM_054027.6 missense
NM_054027.6 missense
Scores
10
7
2
Clinical Significance
Conservation
PhyloP100: 9.20
Genes affected
ANKH (HGNC:15492): (ANKH inorganic pyrophosphate transport regulator) This gene encodes a multipass transmembrane protein that is expressed in joints and other tissues and controls pyrophosphate levels in cultured cells. Progressive ankylosis-mediated control of pyrophosphate levels has been suggested as a possible mechanism regulating tissue calcification and susceptibility to arthritis in higher animals. Mutations in this gene have been associated with autosomal dominant craniometaphyseal dysplasia. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ANKH. . Gene score misZ 2.3499 (greater than the threshold 3.09). Trascript score misZ 3.5351 (greater than threshold 3.09). GenCC has associacion of gene with chondrocalcinosis 2, craniometaphyseal dysplasia, autosomal dominant, craniometaphyseal dysplasia.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.994
PP5
Variant 5-14741837-A-C is Pathogenic according to our data. Variant chr5-14741837-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 5202.Status of the report is no_assertion_criteria_provided, 0 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ANKH | NM_054027.6 | c.1001T>G | p.Leu334Arg | missense_variant | 8/12 | ENST00000284268.8 | NP_473368.1 | |
ANKH | XM_017009644.3 | c.917T>G | p.Leu306Arg | missense_variant | 8/12 | XP_016865133.1 | ||
ANKH | XM_011514067.2 | c.1001T>G | p.Leu334Arg | missense_variant | 8/9 | XP_011512369.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ANKH | ENST00000284268.8 | c.1001T>G | p.Leu334Arg | missense_variant | 8/12 | 1 | NM_054027.6 | ENSP00000284268.6 | ||
ANKH | ENST00000503939.5 | n.513T>G | non_coding_transcript_exon_variant | 5/6 | 3 | |||||
ANKH | ENST00000515517.1 | n.235T>G | non_coding_transcript_exon_variant | 3/3 | 3 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
Cov.:
33
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461590Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 727120
GnomAD4 exome
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1
AN:
1461590
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30
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0
AN XY:
727120
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GnomAD4 genome Cov.: 33
GnomAD4 genome
Cov.:
33
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
Craniometaphyseal dysplasia, autosomal dominant Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 01, 2010 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Pathogenic
D
MutationAssessor
Benign
L
PrimateAI
Pathogenic
T
PROVEAN
Uncertain
D
REVEL
Pathogenic
Sift
Uncertain
D
Sift4G
Uncertain
D
Polyphen
D
Vest4
MutPred
Loss of stability (P = 0.0375);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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Calibrated prediction
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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