NM_054027.6:c.97-45583T>C

Variant names:

• chr5-14814774-A-G
• rs31916
• NM_054027.6:c.97-45583T>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.97-45583T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.27 in 152,106 control chromosomes in the GnomAD database, including 5,743 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 0.27 (5743 hom., cov: 32)
• Consequence: ANKH NM_054027.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.106
• Publications: 8 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=-0.88).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.34 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANKH	NM_054027.6	c.97-45583T>C		intron_variant	Intron 1 of 11	ENST00000284268.8	NP_473368.1
ANKH	XM_011514067.2	c.97-45583T>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.97-45583T>C		intron_variant	Intron 1 of 11	1	NM_054027.6	ENSP00000284268.6
ANKH	ENST00000513115.1	n.122-45583T>C		intron_variant	Intron 1 of 1	2

Frequencies

GnomAD3 genomes AF: 0.270 AC: 41095 AN: 151988 Hom.: 5736 Cov.: 32

Gnomad AFR AF: 0.209

Gnomad AMI AF: 0.369

Gnomad AMR AF: 0.348

Gnomad ASJ AF: 0.326

Gnomad EAS AF: 0.309

Gnomad SAS AF: 0.228

Gnomad FIN AF: 0.270

Gnomad MID AF: 0.212

Gnomad NFE AF: 0.287

Gnomad OTH AF: 0.248

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

GnomAD4 genome AF: 0.270 AC: 41128 AN: 152106 Hom.: 5743 Cov.: 32 AF XY: 0.269 AC XY: 19968 AN XY: 74352

African (AFR) AF: 0.209 AC: 8684 AN: 41492

American (AMR) AF: 0.348 AC: 5321 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.326 AC: 1131 AN: 3468

East Asian (EAS) AF: 0.308 AC: 1598 AN: 5182

South Asian (SAS) AF: 0.230 AC: 1111 AN: 4826

European-Finnish (FIN) AF: 0.270 AC: 2856 AN: 10562

Middle Eastern (MID) AF: 0.201 AC: 59 AN: 294

European-Non Finnish (NFE) AF: 0.287 AC: 19515 AN: 67978

Other (OTH) AF: 0.245 AC: 517 AN: 2106

Alfa AF: 0.285 Hom.: 3577

Bravo AF: 0.270

Asia WGS AF: 0.262 AC: 915 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.6
DANN	Benign	0.59
PhyloP100		-0.11
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: rs31916; hg19: chr5-14814883;