rs121908405

Variant names:

• chr5-14716715-GGAA-G
• rs121908405
• NM_054027.6:c.1129_1131delTTC

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PM4_Supporting PP5_Very_Strong

The NM_054027.6(ANKH):​c.1129_1131delTTC​(p.Phe377del) variant causes a conservative inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ANKH NM_054027.6 conservative_inframe_deletion
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 9.32

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]

OTULIN (HGNC:25118): (OTU deubiquitinase with linear linkage specificity) This gene encodes a member of the peptidase C65 family of ubiquitin isopeptidases. Members of this family remove ubiquitin from proteins. The encoded enzyme specifically recognizes and removes M1(Met1)-linked, or linear, ubiquitin chains from protein substrates. Linear ubiquitin chains are known to regulate the NF-kappa B signaling pathway in the context of immunity and inflammation. Mutations in this gene cause a potentially fatal autoinflammatory syndrome in human patients. [provided by RefSeq, Sep 2016]

LOC100130744 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_054027.6. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 5-14716715-GGAA-G is Pathogenic according to our data. Variant chr5-14716715-GGAA-G is described in ClinVar as [Pathogenic]. Clinvar id is 5191.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-14716715-GGAA-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANKH	NM_054027.6	c.1129_1131delTTC	p.Phe377del	conservative_inframe_deletion	Exon 9 of 12	ENST00000284268.8	NP_473368.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANKH	ENST00000284268.8	c.1129_1131delTTC	p.Phe377del	conservative_inframe_deletion	Exon 9 of 12	1	NM_054027.6	ENSP00000284268.6
ANKH	ENST00000502585.1	n.371_373delTTC		non_coding_transcript_exon_variant	Exon 1 of 4	2

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Craniometaphyseal dysplasia, autosomal dominant Pathogenic:2

Jun 22, 2023

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The observed inframe deletion variant c.1129_1131delp.Phe377del in the ANKH gene has been reported previously in individuals with craniometaphyseal dysplasia. Experimental studies have shown that this variant affects ANKH function Nürnberg P, et al., 2001; Kanaujiya J, et al., 2018. This variant is absent in the gnomAD Exomes. This p.Phe377del causes deletion of amino acid Phenylalanine at position 377. This variant has been reported to the ClinVar database as Pathogenic. This variant is predicted to cause changes in the protein length resulting from in-frame deletion. For these reasons, this variant has been classified as Pathogenic. -

Jun 01, 2001

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:1

Oct 25, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.1129_1131del, results in the deletion of 1 amino acid(s) of the ANKH protein (p.Phe377del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with craniometaphyseal dysplasia (PMID: 11326272). It has also been observed to segregate with disease in related individuals. Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects ANKH function (PMID: 30356088). For these reasons, this variant has been classified as Pathogenic. -

Chondrocalcinosis 2 Pathogenic:1

May 04, 2022

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

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

LitVar

Other links and lift over

dbSNP: rs121908405; hg19: chr5-14716824;