chr5-14705284-T-TA

Position:

• chr5-14705284-T-TA

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_054027.6(ANKH):​c.*5912_*5913insT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00266 in 146,478 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0027 (2 hom., cov: 32)
  • Failed GnomAD Quality Control
• Consequence: ANKH NM_054027.6 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: -0.152

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 Likely_benign. Variant got -5 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00266 (389/146478) while in subpopulation AFR AF= 0.00535 (215/40190). AF 95% confidence interval is 0.00476. There are 2 homozygotes in gnomad4. There are 177 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 389 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANKH	NM_054027.6	c.*5912_*5913insT		3_prime_UTR_variant	12/12	ENST00000284268.8	NP_473368.1
ANKH	XM_017009644.3	c.*5912_*5913insT		3_prime_UTR_variant	12/12		XP_016865133.1
OTULIN	XM_011514151.3	c.*47-7425dup		intron_variant			XP_011512453.1
OTULIN	XR_007058658.1	n.1214-3641dup		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ANKH	ENST00000284268.8	c.*5912_*5913insT		3_prime_UTR_variant	12/12	1	NM_054027.6	ENSP00000284268	P1

Frequencies

GnomAD3 genomes AF: 0.00262 AC: 383 AN: 146408 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00521

Gnomad AMI AF: 0.0210

Gnomad AMR AF: 0.00348

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000783

Gnomad SAS AF: 0.000859

Gnomad FIN AF: 0.000330

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00131

Gnomad OTH AF: 0.00299

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

GnomAD4 genome AF: 0.00266 AC: 389 AN: 146478 Hom.: 2 Cov.: 32 AF XY: 0.00249 AC XY: 177 AN XY: 71216

Gnomad4 AFR AF: 0.00535

Gnomad4 AMR AF: 0.00347

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000785

Gnomad4 SAS AF: 0.000861

Gnomad4 FIN AF: 0.000330

Gnomad4 NFE AF: 0.00132

Gnomad4 OTH AF: 0.00297

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

Chondrocalcinosis Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Craniometadiaphyseal dysplasia wormian bone type Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

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: rs765143871; hg19: chr5-14705393;