rs26307

Variant names:

• chr5-14705556-T-C
• rs26307
• NM_054027.6:c.*5641A>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.*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, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.39
• Publications: 12 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]

OTULIN (HGNC:25118): (OTU deubiquitinase with linear linkage specificity) This gene encodes a member of the peptidase C65 family of ubiquitin isopeptidases. Members of this family remove ubiquitin from proteins. The encoded enzyme specifically recognizes and removes M1(Met1)-linked, or linear, ubiquitin chains from protein substrates. Linear ubiquitin chains are known to regulate the NF-kappa B signaling pathway in the context of immunity and inflammation. Mutations in this gene cause a potentially fatal autoinflammatory syndrome in human patients. [provided by RefSeq, Sep 2016]

OTULIN Gene-Disease associations (from GenCC):

• autoinflammation, panniculitis, and dermatosis syndrome, autosomal recessive

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
• hereditary periodic fever syndrome

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• immunodeficiency 107, susceptibility to invasive staphylococcus aureus infection

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 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 VariationId is 351403.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.808 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_054027.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANKH	NM_054027.6	MANE Select	c.*5641A>G		3_prime_UTR	Exon 12 of 12	NP_473368.1	Q9HCJ1-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANKH	ENST00000284268.8	TSL:1 MANE Select	c.*5641A>G		3_prime_UTR	Exon 12 of 12	ENSP00000284268.6	Q9HCJ1-1
	OTULIN	ENST00000850613.1		c.*47-7166T>C		intron	N/A	ENSP00000520900.1	Q96BN8
	OTULIN	ENST00000921417.1		c.*47-7166T>C		intron	N/A	ENSP00000591476.1

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

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.813 AC: 13 AN: 16

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.833 AC: 5 AN: 6

Other (OTH) AF: 1.00 AC: 2 AN: 2

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

African (AFR) AF: 0.516 AC: 21397 AN: 41490

American (AMR) AF: 0.785 AC: 12006 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.878 AC: 3047 AN: 3470

East Asian (EAS) AF: 0.761 AC: 3935 AN: 5168

South Asian (SAS) AF: 0.829 AC: 4000 AN: 4824

European-Finnish (FIN) AF: 0.854 AC: 9064 AN: 10608

Middle Eastern (MID) AF: 0.854 AC: 251 AN: 294

European-Non Finnish (NFE) AF: 0.790 AC: 53729 AN: 67992

Other (OTH) AF: 0.746 AC: 1576 AN: 2112

Alfa AF: 0.758 Hom.: 13241

Bravo AF: 0.707

Asia WGS AF: 0.748 AC: 2600 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Chondrocalcinosis 2 (1)
-	-	1	Craniometaphyseal dysplasia, autosomal dominant (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.11
DANN	Benign	0.30
PhyloP100		-1.4
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: rs26307; hg19: chr5-14705665;