rs121908405

chr5-14716715-GGAA-G

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM2 PM4_Supporting PP5_Very_Strong

The NM_054027.6(ANKH):c.1129_1131del(p.Phe377del) variant causes a 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 inframe_deletion
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• 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]

ACMG classification

Verdict is Pathogenic. Variant got 13 ACMG points.

• PM1: In a topological_domain Cytoplasmic (size 31) in uniprot entity ANKH_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_054027.6
• 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/exons	MANE	UniProt
ANKH	NM_054027.6	c.1129_1131del	p.Phe377del	inframe_deletion	9/12	ENST00000284268.8
ANKH	XM_017009644.3	c.1045_1047del	p.Phe349del	inframe_deletion	9/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANKH	ENST00000284268.8	c.1129_1131del	p.Phe377del	inframe_deletion	9/12	1	NM_054027.6	P1
ANKH	ENST00000502585.1	n.371_373del		non_coding_transcript_exon_variant	1/4	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:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Oct 25, 2023

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. -

Craniometaphyseal dysplasia, autosomal dominant Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 01, 2001

- -

Chondrocalcinosis 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

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;