chr5-14871451-C-T

Variant names:

• chr5-14871451-C-T
• rs78431233
• NM_054027.6:c.-4G>A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_054027.6(ANKH):​c.-4G>A variant causes a 5 prime UTR change. The variant allele was found at a frequency of 0.0684 in 1,610,634 control chromosomes in the GnomAD database, including 4,327 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.053 (334 hom., cov: 32)
  • Exomes 𝑓: 0.070 (3993 hom.)
• Consequence: ANKH NM_054027.6 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 3.72

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 Benign. Variant got -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 5-14871451-C-T is Benign according to our data. Variant chr5-14871451-C-T is described in ClinVar as [Benign]. Clinvar id is 351926.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0817 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANKH	NM_054027.6	c.-4G>A		5_prime_UTR_variant	Exon 1 of 12	ENST00000284268.8	NP_473368.1
ANKH	XM_011514067.2	c.-4G>A		5_prime_UTR_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.-4G>A		5_prime_UTR_variant	Exon 1 of 12	1	NM_054027.6	ENSP00000284268.6
ANKH	ENST00000505140.1	n.-4G>A		non_coding_transcript_exon_variant	Exon 1 of 2	5		ENSP00000426332.1
ANKH	ENST00000513115.1	n.22G>A		non_coding_transcript_exon_variant	Exon 1 of 2	2
ANKH	ENST00000505140.1	n.-4G>A		5_prime_UTR_variant	Exon 1 of 2	5		ENSP00000426332.1

Frequencies

GnomAD3 genomes AF: 0.0529 AC: 8041 AN: 151890 Hom.: 334 Cov.: 32

Gnomad AFR AF: 0.0138

Gnomad AMI AF: 0.134

Gnomad AMR AF: 0.0360

Gnomad ASJ AF: 0.0374

Gnomad EAS AF: 0.000195

Gnomad SAS AF: 0.0226

Gnomad FIN AF: 0.0708

Gnomad MID AF: 0.0865

Gnomad NFE AF: 0.0835

Gnomad OTH AF: 0.0527

GnomAD3 exomes AF: 0.0544 AC: 13441 AN: 247074 Hom.: 448 AF XY: 0.0563 AC XY: 7561 AN XY: 134316

Gnomad AFR exome AF: 0.0120

Gnomad AMR exome AF: 0.0276

Gnomad ASJ exome AF: 0.0390

Gnomad EAS exome AF: 0.000110

Gnomad SAS exome AF: 0.0276

Gnomad FIN exome AF: 0.0761

Gnomad NFE exome AF: 0.0823

Gnomad OTH exome AF: 0.0562

GnomAD4 exome AF: 0.0700 AC: 102171 AN: 1458632 Hom.: 3993 Cov.: 31 AF XY: 0.0695 AC XY: 50463 AN XY: 725692

Gnomad4 AFR exome AF: 0.0112

Gnomad4 AMR exome AF: 0.0294

Gnomad4 ASJ exome AF: 0.0403

Gnomad4 EAS exome AF: 0.000177

Gnomad4 SAS exome AF: 0.0287

Gnomad4 FIN exome AF: 0.0779

Gnomad4 NFE exome AF: 0.0798

Gnomad4 OTH exome AF: 0.0631

GnomAD4 genome AF: 0.0529 AC: 8036 AN: 152002 Hom.: 334 Cov.: 32 AF XY: 0.0508 AC XY: 3775 AN XY: 74306

Gnomad4 AFR AF: 0.0138

Gnomad4 AMR AF: 0.0359

Gnomad4 ASJ AF: 0.0374

Gnomad4 EAS AF: 0.000195

Gnomad4 SAS AF: 0.0222

Gnomad4 FIN AF: 0.0708

Gnomad4 NFE AF: 0.0835

Gnomad4 OTH AF: 0.0521

Alfa AF: 0.0681 Hom.: 156

Bravo AF: 0.0472

Asia WGS AF: 0.0100 AC: 35 AN: 3478

EpiCase AF: 0.0800

EpiControl AF: 0.0811

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Dec 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 15818664, 21811784, 23315997) -

Oct 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Craniometaphyseal dysplasia, autosomal dominant Benign:2

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Chondrocalcinosis 2 Benign:1

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	22
DANN	Benign	0.74

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: rs78431233; hg19: chr5-14871560;