rs27911

Positions:

• chr5-14707269-G-A
• chr5-14707269-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_054027.6(ANKH):​c.*3928C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.871 in 149,208 control chromosomes in the GnomAD database, including 55,785 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.87 (55784 hom., cov: 28)
  • Exomes 𝑓: 1.0 (1 hom.)
• Consequence: ANKH NM_054027.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.944

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 5-14707269-G-A is Benign according to our data. Variant chr5-14707269-G-A is described in ClinVar as [Benign]. Clinvar id is 351424.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.898 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANKH	NM_054027.6	c.*3928C>T		3_prime_UTR_variant	12/12	ENST00000284268.8	NP_473368.1
ANKH	XM_017009644.3	c.*3928C>T		3_prime_UTR_variant	12/12		XP_016865133.1
OTULIN	XM_011514151.3	c.*47-5453G>A		intron_variant			XP_011512453.1
OTULIN	XR_007058658.1	n.1214-1669G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ANKH	ENST00000284268.8	c.*3928C>T		3_prime_UTR_variant	12/12	1	NM_054027.6	ENSP00000284268	P1

Frequencies

GnomAD3 genomes AF: 0.871 AC: 129921 AN: 149092 Hom.: 55747 Cov.: 28

Gnomad AFR AF: 0.890

Gnomad AMI AF: 0.888

Gnomad AMR AF: 0.911

Gnomad ASJ AF: 0.905

Gnomad EAS AF: 0.798

Gnomad SAS AF: 0.899

Gnomad FIN AF: 0.880

Gnomad MID AF: 0.911

Gnomad NFE AF: 0.852

Gnomad OTH AF: 0.869

GnomAD4 exome AF: 1.00 AC: 2 AN: 2 Hom.: 1 Cov.: 0 AC XY: 0 AN XY: 0

Gnomad4 FIN exome AF: 1.00

GnomAD4 genome AF: 0.871 AC: 130009 AN: 149206 Hom.: 55784 Cov.: 28 AF XY: 0.873 AC XY: 63655 AN XY: 72914

Gnomad4 AFR AF: 0.890

Gnomad4 AMR AF: 0.911

Gnomad4 ASJ AF: 0.905

Gnomad4 EAS AF: 0.797

Gnomad4 SAS AF: 0.899

Gnomad4 FIN AF: 0.880

Gnomad4 NFE AF: 0.852

Gnomad4 OTH AF: 0.861

Alfa AF: 0.927 Hom.: 81244

Bravo AF: 0.862

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

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	-0.89
CADD	Benign	0.080
DANN	Benign	0.63

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: rs27911; hg19: chr5-14707378;