rs2291943

Positions:

• chr5-14751291-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_054027.6(ANKH):​c.517-52A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0812 in 1,575,912 control chromosomes in the GnomAD database, including 11,367 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.17 (4198 hom., cov: 33)
  • Exomes 𝑓: 0.072 (7169 hom.)
• Consequence: ANKH NM_054027.6 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.70

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 5-14751291-T-C is Benign according to our data. Variant chr5-14751291-T-C is described in ClinVar as [Benign]. Clinvar id is 1238126.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.414 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANKH	NM_054027.6	c.517-52A>G		intron_variant		ENST00000284268.8
ANKH	XM_011514067.2	c.517-52A>G		intron_variant
ANKH	XM_017009644.3	c.433-52A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANKH	ENST00000284268.8	c.517-52A>G		intron_variant		1	NM_054027.6	P1
ANKH	ENST00000503939.5	n.29-52A>G		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.171 AC: 25944 AN: 152054 Hom.: 4167 Cov.: 33

Gnomad AFR AF: 0.418

Gnomad AMI AF: 0.0669

Gnomad AMR AF: 0.199

Gnomad ASJ AF: 0.0737

Gnomad EAS AF: 0.101

Gnomad SAS AF: 0.0596

Gnomad FIN AF: 0.0468

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0543

Gnomad OTH AF: 0.132

GnomAD3 exomes AF: 0.115 AC: 27890 AN: 241628 Hom.: 3221 AF XY: 0.0996 AC XY: 13029 AN XY: 130864

Gnomad AFR exome AF: 0.428

Gnomad AMR exome AF: 0.291

Gnomad ASJ exome AF: 0.0687

Gnomad EAS exome AF: 0.105

Gnomad SAS exome AF: 0.0551

Gnomad FIN exome AF: 0.0428

Gnomad NFE exome AF: 0.0542

Gnomad OTH exome AF: 0.0841

GnomAD4 exome AF: 0.0716 AC: 101959 AN: 1423740 Hom.: 7169 Cov.: 24 AF XY: 0.0690 AC XY: 48967 AN XY: 709966

Gnomad4 AFR exome AF: 0.430

Gnomad4 AMR exome AF: 0.278

Gnomad4 ASJ exome AF: 0.0736

Gnomad4 EAS exome AF: 0.105

Gnomad4 SAS exome AF: 0.0550

Gnomad4 FIN exome AF: 0.0445

Gnomad4 NFE exome AF: 0.0532

Gnomad4 OTH exome AF: 0.0831

GnomAD4 genome AF: 0.171 AC: 26035 AN: 152172 Hom.: 4198 Cov.: 33 AF XY: 0.169 AC XY: 12549 AN XY: 74420

Gnomad4 AFR AF: 0.419

Gnomad4 AMR AF: 0.200

Gnomad4 ASJ AF: 0.0737

Gnomad4 EAS AF: 0.101

Gnomad4 SAS AF: 0.0597

Gnomad4 FIN AF: 0.0468

Gnomad4 NFE AF: 0.0543

Gnomad4 OTH AF: 0.131

Alfa AF: 0.0822 Hom.: 1143

Bravo AF: 0.197

Asia WGS AF: 0.111 AC: 387 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 10, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.22
DANN	Benign	0.35

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

Publications

LitVar

Other links and lift over

dbSNP: rs2291943; hg19: chr5-14751400; COSMIC: COSV52478581; COSMIC: COSV52478581;