rs258360

Variant names:

• chr5-14763677-G-T
• rs258360
• NM_054027.6:c.314-5079C>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_054027.6(ANKH):​c.314-5079C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.204 in 152,226 control chromosomes in the GnomAD database, including 3,331 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.20 (3331 hom., cov: 33)
• Consequence: ANKH NM_054027.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.512
• Publications: 3 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: Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P
• 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.28 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANKH	NM_054027.6	MANE Select	c.314-5079C>A		intron	N/A	NP_473368.1	Q9HCJ1-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANKH	ENST00000284268.8	TSL:1 MANE Select	c.314-5079C>A		intron	N/A	ENSP00000284268.6	Q9HCJ1-1
	ANKH	ENST00000887636.1		c.314-5079C>A		intron	N/A	ENSP00000557695.1
	ANKH	ENST00000964374.1		c.314-5079C>A		intron	N/A	ENSP00000634433.1

Frequencies

GnomAD3 genomes AF: 0.204 AC: 31018 AN: 152108 Hom.: 3328 Cov.: 33

Gnomad AFR AF: 0.226

Gnomad AMI AF: 0.124

Gnomad AMR AF: 0.168

Gnomad ASJ AF: 0.216

Gnomad EAS AF: 0.0229

Gnomad SAS AF: 0.292

Gnomad FIN AF: 0.125

Gnomad MID AF: 0.317

Gnomad NFE AF: 0.217

Gnomad OTH AF: 0.239

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

GnomAD4 genome AF: 0.204 AC: 31038 AN: 152226 Hom.: 3331 Cov.: 33 AF XY: 0.201 AC XY: 14966 AN XY: 74426

African (AFR) AF: 0.226 AC: 9390 AN: 41522

American (AMR) AF: 0.167 AC: 2559 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.216 AC: 749 AN: 3468

East Asian (EAS) AF: 0.0227 AC: 118 AN: 5188

South Asian (SAS) AF: 0.292 AC: 1409 AN: 4822

European-Finnish (FIN) AF: 0.125 AC: 1327 AN: 10610

Middle Eastern (MID) AF: 0.328 AC: 95 AN: 290

European-Non Finnish (NFE) AF: 0.217 AC: 14770 AN: 68002

Other (OTH) AF: 0.241 AC: 508 AN: 2112

Alfa AF: 0.213 Hom.: 6759

Bravo AF: 0.204

Asia WGS AF: 0.184 AC: 641 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.56
DANN	Benign	0.53
PhyloP100		-0.51
Mutation Taster		=100/0	polymorphism (auto)

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: rs258360; hg19: chr5-14763786;