5-14743346-G-T

Variant names:

• chr5-14743346-G-T
• rs697565
• NM_054027.6:c.916-1424C>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.916-1424C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.188 in 152,096 control chromosomes in the GnomAD database, including 2,876 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 0.19 (2876 hom., cov: 33)
• Consequence: ANKH NM_054027.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.52
• Publications: 2 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=-0.88).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.242 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.916-1424C>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.916-1424C>A		intron	N/A	ENSP00000284268.6	Q9HCJ1-1
	ANKH	ENST00000887636.1		c.916-1424C>A		intron	N/A	ENSP00000557695.1
	ANKH	ENST00000964374.1		c.916-1424C>A		intron	N/A	ENSP00000634433.1

Frequencies

GnomAD3 genomes AF: 0.188 AC: 28524 AN: 151978 Hom.: 2879 Cov.: 33

Gnomad AFR AF: 0.246

Gnomad AMI AF: 0.185

Gnomad AMR AF: 0.142

Gnomad ASJ AF: 0.142

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.0375

Gnomad FIN AF: 0.206

Gnomad MID AF: 0.158

Gnomad NFE AF: 0.187

Gnomad OTH AF: 0.192

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

GnomAD4 genome AF: 0.188 AC: 28538 AN: 152096 Hom.: 2876 Cov.: 33 AF XY: 0.184 AC XY: 13669 AN XY: 74340

African (AFR) AF: 0.246 AC: 10206 AN: 41488

American (AMR) AF: 0.142 AC: 2174 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.142 AC: 494 AN: 3472

East Asian (EAS) AF: 0.000579 AC: 3 AN: 5180

South Asian (SAS) AF: 0.0373 AC: 180 AN: 4820

European-Finnish (FIN) AF: 0.206 AC: 2172 AN: 10564

Middle Eastern (MID) AF: 0.163 AC: 48 AN: 294

European-Non Finnish (NFE) AF: 0.187 AC: 12693 AN: 67974

Other (OTH) AF: 0.189 AC: 399 AN: 2110

Alfa AF: 0.138 Hom.: 336

Bravo AF: 0.190

Asia WGS AF: 0.0370 AC: 133 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	3.8
DANN	Benign	0.50
PhyloP100		1.5
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: rs697565; hg19: chr5-14743455;