rs26307

Positions:

• chr5-14705556-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.*5641A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.721 in 152,188 control chromosomes in the GnomAD database, including 40,785 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.72 (40777 hom., cov: 33)
  • Exomes 𝑓: 0.83 (8 hom.)
• Consequence: ANKH NM_054027.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -1.39

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]

OTULIN (HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 5-14705556-T-C is Benign according to our data. Variant chr5-14705556-T-C is described in ClinVar as [Benign]. Clinvar id is 351403.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.808 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANKH	NM_054027.6	c.*5641A>G		3_prime_UTR_variant	12/12	ENST00000284268.8
ANKH	XM_017009644.3	c.*5641A>G		3_prime_UTR_variant	12/12
OTULIN	XM_011514151.3	c.*47-7166T>C		intron_variant
OTULIN	XR_007058658.1	n.1214-3382T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANKH	ENST00000284268.8	c.*5641A>G		3_prime_UTR_variant	12/12	1	NM_054027.6	P1

Frequencies

GnomAD3 genomes AF: 0.722 AC: 109714 AN: 152046 Hom.: 40774 Cov.: 33

Gnomad AFR AF: 0.516

Gnomad AMI AF: 0.813

Gnomad AMR AF: 0.785

Gnomad ASJ AF: 0.878

Gnomad EAS AF: 0.762

Gnomad SAS AF: 0.829

Gnomad FIN AF: 0.854

Gnomad MID AF: 0.858

Gnomad NFE AF: 0.790

Gnomad OTH AF: 0.754

GnomAD4 exome AF: 0.833 AC: 20 AN: 24 Hom.: 8 Cov.: 0 AF XY: 0.750 AC XY: 9 AN XY: 12

Gnomad4 FIN exome AF: 0.813

Gnomad4 NFE exome AF: 0.833

Gnomad4 OTH exome AF: 1.00

GnomAD4 genome AF: 0.721 AC: 109746 AN: 152164 Hom.: 40777 Cov.: 33 AF XY: 0.728 AC XY: 54164 AN XY: 74392

Gnomad4 AFR AF: 0.516

Gnomad4 AMR AF: 0.785

Gnomad4 ASJ AF: 0.878

Gnomad4 EAS AF: 0.761

Gnomad4 SAS AF: 0.829

Gnomad4 FIN AF: 0.854

Gnomad4 NFE AF: 0.790

Gnomad4 OTH AF: 0.746

Alfa AF: 0.752 Hom.: 6997

Bravo AF: 0.707

Asia WGS AF: 0.748 AC: 2600 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

Craniometaphyseal dysplasia, autosomal dominant Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Chondrocalcinosis 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.11
DANN	Benign	0.30

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: rs26307; hg19: chr5-14705665;