NM_054027.6:c.13C>T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PM5 PP5

The NM_054027.6(ANKH):​c.13C>T​(p.Pro5Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P5L) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ANKH NM_054027.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 5.08

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 Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-14871434-G-A is described in Lovd as [Pathogenic].
• PP5: Variant 5-14871435-G-A is Pathogenic according to our data. Variant chr5-14871435-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 974898.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANKH	NM_054027.6	c.13C>T	p.Pro5Ser	missense_variant	Exon 1 of 12	ENST00000284268.8	NP_473368.1
ANKH	XM_011514067.2	c.13C>T	p.Pro5Ser	missense_variant	Exon 1 of 9		XP_011512369.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANKH	ENST00000284268.8	c.13C>T	p.Pro5Ser	missense_variant	Exon 1 of 12	1	NM_054027.6	ENSP00000284268.6
ANKH	ENST00000505140.1	n.13C>T		non_coding_transcript_exon_variant	Exon 1 of 2	5		ENSP00000426332.1
ANKH	ENST00000513115.1	n.38C>T		non_coding_transcript_exon_variant	Exon 1 of 2	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Chondrocalcinosis 2 Pathogenic:1

-

Centogene AG - the Rare Disease Company

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1

Nov 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 5 of the ANKH protein (p.Pro5Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of ANKH-related conditions (PMID: 22647861, 32860008; internal data). ClinVar contains an entry for this variant (Variation ID: 974898). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. This variant disrupts the p.P5 amino acid residue in ANKH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12297989). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.17
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.44	T
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.032
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.84	T
M_CAP	Pathogenic	0.88	D
MetaRNN	Uncertain	0.74	D
MetaSVM	Uncertain	0.29	D
MutationAssessor	Benign	0.81	L
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	0.67	N
REVEL	Uncertain	0.63
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.085	B
Vest4		0.63
MutPred		0.64		Gain of glycosylation at P5 (P = 0.0152);
MVP		0.87
MPC		2.0
ClinPred		0.60	D
GERP RS		4.1
Varity_R		0.41
gMVP		0.71

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: rs121908410; hg19: chr5-14871544;