5-14869600-A-G

Variant names:

• chr5-14869600-A-G
• rs3006069
• NM_054027.6:c.96+1752T>C

Variant summary

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

The NM_054027.6(ANKH):​c.96+1752T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.449 in 152,114 control chromosomes in the GnomAD database, including 15,464 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 0.45 (15464 hom., cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ANKH NM_054027.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.856
• Publications: 15 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=-0.83).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.48 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANKH	NM_054027.6	c.96+1752T>C		intron_variant	Intron 1 of 11	ENST00000284268.8	NP_473368.1
ANKH	XM_011514067.2	c.96+1752T>C		intron_variant	Intron 1 of 8		XP_011512369.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANKH	ENST00000284268.8	c.96+1752T>C		intron_variant	Intron 1 of 11	1	NM_054027.6	ENSP00000284268.6
ANKH	ENST00000647541.1	n.763T>C		non_coding_transcript_exon_variant	Exon 1 of 1
ANKH	ENST00000505140.1	n.*885-570T>C		intron_variant	Intron 1 of 1	5		ENSP00000426332.1
ANKH	ENST00000513115.1	n.121+1752T>C		intron_variant	Intron 1 of 1	2

Frequencies

GnomAD3 genomes AF: 0.449 AC: 68189 AN: 151996 Hom.: 15459 Cov.: 33

Gnomad AFR AF: 0.427

Gnomad AMI AF: 0.650

Gnomad AMR AF: 0.489

Gnomad ASJ AF: 0.490

Gnomad EAS AF: 0.319

Gnomad SAS AF: 0.403

Gnomad FIN AF: 0.402

Gnomad MID AF: 0.579

Gnomad NFE AF: 0.467

Gnomad OTH AF: 0.473

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 2 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.449 AC: 68232 AN: 152114 Hom.: 15464 Cov.: 33 AF XY: 0.445 AC XY: 33115 AN XY: 74366

African (AFR) AF: 0.428 AC: 17737 AN: 41468

American (AMR) AF: 0.489 AC: 7483 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.490 AC: 1700 AN: 3470

East Asian (EAS) AF: 0.319 AC: 1657 AN: 5188

South Asian (SAS) AF: 0.402 AC: 1938 AN: 4822

European-Finnish (FIN) AF: 0.402 AC: 4252 AN: 10572

Middle Eastern (MID) AF: 0.565 AC: 166 AN: 294

European-Non Finnish (NFE) AF: 0.467 AC: 31720 AN: 67982

Other (OTH) AF: 0.467 AC: 986 AN: 2112

Alfa AF: 0.461 Hom.: 44804

Bravo AF: 0.454

Asia WGS AF: 0.359 AC: 1247 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	5.7
DANN	Benign	0.82
PhyloP100		0.86
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: rs3006069; hg19: chr5-14869709;