5-14871435-G-T

Variant names:

• chr5-14871435-G-T
• rs121908410
• NM_054027.6:c.13C>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PM5 PP3 PP5

The NM_054027.6(ANKH):​c.13C>A​(p.Pro5Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,460,586 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 Likely pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P5S) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ANKH NM_054027.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 5.08
• Publications: 5 publications found

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]

ANKH Gene-Disease associations (from GenCC):

• chondrocalcinosis 2

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp
• craniometaphyseal dysplasia, autosomal dominant

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)
• skeletal dysplasia

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• craniometaphyseal dysplasia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-14871435-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 974898.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.823
• PP5: Variant 5-14871435-G-T is Pathogenic according to our data. Variant chr5-14871435-G-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 5199.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_054027.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANKH	NM_054027.6	MANE Select	c.13C>A	p.Pro5Thr	missense	Exon 1 of 12	NP_473368.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANKH	ENST00000284268.8	TSL:1 MANE Select	c.13C>A	p.Pro5Thr	missense	Exon 1 of 12	ENSP00000284268.6
	ANKH	ENST00000505140.1	TSL:5	n.13C>A		non_coding_transcript_exon	Exon 1 of 2	ENSP00000426332.1
	ANKH	ENST00000513115.1	TSL:2	n.38C>A		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460586 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 726634

African (AFR) AF: 0.00 AC: 0 AN: 33450

American (AMR) AF: 0.00 AC: 0 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26096

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.00 AC: 0 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53106

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111248

Other (OTH) AF: 0.00 AC: 0 AN: 60300

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

ANKH-related disorder Pathogenic:1

Sep 17, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The ANKH c.13C>A variant is predicted to result in the amino acid substitution p.Pro5Thr. This variant has been reported to segregate with disease in two families with chondrocalcinosis (Williams et al. 2003. PubMed ID: 13130483). Additionally, alternate missense variants affecting this amino acid (p.Pro5Leu, p.Pro5Ser) have been reported as pathogenic (Williams et al. 2002. PubMed ID: 12297989; Gruber et al. 2012. PubMed ID: 22647861). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as likely pathogenic.

Chondrocalcinosis 2 Pathogenic:1

Sep 01, 2003

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.23
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.44	T
Eigen	Benign	-0.072
Eigen_PC	Benign	-0.0037
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.79	T
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Uncertain	0.58	D
MutationAssessor	Benign	0.81	L
PhyloP100		5.1
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	0.080	N
REVEL	Pathogenic	0.65
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.16	B
Vest4		0.74
MutPred		0.69		Gain of MoRF binding (P = 0.0762)
MVP		0.88
MPC		2.1
ClinPred		0.59	D
GERP RS		4.1
PromoterAI		0.072	Neutral
Varity_R		0.45
gMVP		0.71
Mutation Taster		=17/83	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121908410; hg19: chr5-14871544;