chr5-14751291-T-C

Variant names:

• chr5-14751291-T-C
• rs2291943
• NM_054027.6:c.517-52A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong 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, multiple submitters, no conflicts B:2
• 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

Our verdict: Benign. The variant received -20 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_multiple_submitters_no_conflicts, 2 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 rank	MANE	Protein	UniProt
ANKH	NM_054027.6	c.517-52A>G		intron_variant	Intron 4 of 11	ENST00000284268.8	NP_473368.1
ANKH	XM_017009644.3	c.433-52A>G		intron_variant	Intron 4 of 11		XP_016865133.1
ANKH	XM_011514067.2	c.517-52A>G		intron_variant	Intron 4 of 8		XP_011512369.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANKH	ENST00000284268.8	c.517-52A>G		intron_variant	Intron 4 of 11	1	NM_054027.6	ENSP00000284268.6
ANKH	ENST00000503939.5	n.29-52A>G		intron_variant	Intron 1 of 5	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

GnomAD2 exomes AF: 0.115 AC: 27890 AN: 241628 AF XY: 0.0996

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 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

African (AFR) AF: 0.430 AC: 14069 AN: 32718

American (AMR) AF: 0.278 AC: 12230 AN: 43916

Ashkenazi Jewish (ASJ) AF: 0.0736 AC: 1905 AN: 25900

East Asian (EAS) AF: 0.105 AC: 4157 AN: 39446

South Asian (SAS) AF: 0.0550 AC: 4663 AN: 84756

European-Finnish (FIN) AF: 0.0445 AC: 2329 AN: 52284

Middle Eastern (MID) AF: 0.0503 AC: 254 AN: 5048

European-Non Finnish (NFE) AF: 0.0532 AC: 57437 AN: 1080504

Other (OTH) AF: 0.0831 AC: 4915 AN: 59168

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

African (AFR) AF: 0.419 AC: 17375 AN: 41448

American (AMR) AF: 0.200 AC: 3051 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0737 AC: 256 AN: 3472

East Asian (EAS) AF: 0.101 AC: 523 AN: 5180

South Asian (SAS) AF: 0.0597 AC: 288 AN: 4826

European-Finnish (FIN) AF: 0.0468 AC: 497 AN: 10620

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.0543 AC: 3691 AN: 68016

Other (OTH) AF: 0.131 AC: 278 AN: 2116

Alfa AF: 0.0997 Hom.: 2198

Bravo AF: 0.197

Asia WGS AF: 0.111 AC: 387 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.22
DANN	Benign	0.35
PhyloP100		-1.7
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

Publications

LitVar

Other links and lift over

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