5-14751479-T-G

Variant names:

• chr5-14751479-T-G
• rs697571
• NM_054027.6:c.517-240A>C

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.517-240A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.254 in 152,184 control chromosomes in the GnomAD database, including 5,372 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.25 (5372 hom., cov: 33)
• Consequence: ANKH NM_054027.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.53
• Publications: 4 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.01).
• BP6: Variant 5-14751479-T-G is Benign according to our data. Variant chr5-14751479-T-G is described in ClinVar as [Benign]. Clinvar id is 1261660.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.353 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANKH	NM_054027.6	c.517-240A>C		intron_variant	Intron 4 of 11	ENST00000284268.8	NP_473368.1
ANKH	XM_017009644.3	c.433-240A>C		intron_variant	Intron 4 of 11		XP_016865133.1
ANKH	XM_011514067.2	c.517-240A>C		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.517-240A>C		intron_variant	Intron 4 of 11	1	NM_054027.6	ENSP00000284268.6
ANKH	ENST00000503939.5	n.29-240A>C		intron_variant	Intron 1 of 5	3

Frequencies

GnomAD3 genomes AF: 0.254 AC: 38627 AN: 152066 Hom.: 5366 Cov.: 33

Gnomad AFR AF: 0.358

Gnomad AMI AF: 0.241

Gnomad AMR AF: 0.302

Gnomad ASJ AF: 0.156

Gnomad EAS AF: 0.105

Gnomad SAS AF: 0.0797

Gnomad FIN AF: 0.233

Gnomad MID AF: 0.180

Gnomad NFE AF: 0.213

Gnomad OTH AF: 0.255

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

GnomAD4 genome AF: 0.254 AC: 38667 AN: 152184 Hom.: 5372 Cov.: 33 AF XY: 0.251 AC XY: 18695 AN XY: 74410

African (AFR) AF: 0.358 AC: 14838 AN: 41486

American (AMR) AF: 0.302 AC: 4612 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.156 AC: 543 AN: 3470

East Asian (EAS) AF: 0.105 AC: 545 AN: 5192

South Asian (SAS) AF: 0.0800 AC: 386 AN: 4828

European-Finnish (FIN) AF: 0.233 AC: 2465 AN: 10590

Middle Eastern (MID) AF: 0.187 AC: 55 AN: 294

European-Non Finnish (NFE) AF: 0.213 AC: 14471 AN: 68012

Other (OTH) AF: 0.252 AC: 533 AN: 2114

Alfa AF: 0.256 Hom.: 2310

Bravo AF: 0.272

Asia WGS AF: 0.123 AC: 433 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	-1.0
CADD	Benign	0.039
DANN	Benign	0.43
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: rs697571; hg19: chr5-14751588; COSMIC: COSV107315476; COSMIC: COSV107315476;