rs4702049

Variant names:

• chr5-14759137-C-T
• rs4702049
• NM_054027.6:c.314-539G>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.314-539G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.385 in 152,054 control chromosomes in the GnomAD database, including 11,490 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 0.38 (11490 hom., cov: 32)
• Consequence: ANKH NM_054027.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.444
• Publications: 4 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.468 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANKH	NM_054027.6	c.314-539G>A		intron_variant	Intron 2 of 11	ENST00000284268.8	NP_473368.1
ANKH	XM_017009644.3	c.230-539G>A		intron_variant	Intron 2 of 11		XP_016865133.1
ANKH	XM_011514067.2	c.314-539G>A		intron_variant	Intron 2 of 8		XP_011512369.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANKH	ENST00000284268.8	c.314-539G>A		intron_variant	Intron 2 of 11	1	NM_054027.6	ENSP00000284268.6

Frequencies

GnomAD3 genomes AF: 0.385 AC: 58485 AN: 151934 Hom.: 11475 Cov.: 32

Gnomad AFR AF: 0.361

Gnomad AMI AF: 0.420

Gnomad AMR AF: 0.477

Gnomad ASJ AF: 0.313

Gnomad EAS AF: 0.331

Gnomad SAS AF: 0.344

Gnomad FIN AF: 0.405

Gnomad MID AF: 0.301

Gnomad NFE AF: 0.387

Gnomad OTH AF: 0.345

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

GnomAD4 genome AF: 0.385 AC: 58536 AN: 152054 Hom.: 11490 Cov.: 32 AF XY: 0.385 AC XY: 28633 AN XY: 74306

African (AFR) AF: 0.362 AC: 14995 AN: 41474

American (AMR) AF: 0.478 AC: 7298 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.313 AC: 1086 AN: 3472

East Asian (EAS) AF: 0.331 AC: 1713 AN: 5174

South Asian (SAS) AF: 0.344 AC: 1659 AN: 4822

European-Finnish (FIN) AF: 0.405 AC: 4270 AN: 10538

Middle Eastern (MID) AF: 0.293 AC: 86 AN: 294

European-Non Finnish (NFE) AF: 0.387 AC: 26327 AN: 67982

Other (OTH) AF: 0.342 AC: 721 AN: 2110

Alfa AF: 0.385 Hom.: 41352

Bravo AF: 0.390

Asia WGS AF: 0.319 AC: 1108 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	2.9
DANN	Benign	0.66
PhyloP100		0.44
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: rs4702049; hg19: chr5-14759246;