rs27911

Variant names:

• chr5-14707269-G-A
• rs27911
• NM_054027.6:c.*3928C>T

Your query was ambiguous. Multiple possible variants found:

• chr5-14707269-G-A
• chr5-14707269-G-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.*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
• Publications: 7 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: Ambry Genetics, G2P, 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=-0.89).
• BP6: Variant 5-14707269-G-A is Benign according to our data. Variant chr5-14707269-G-A is described in ClinVar as Benign. ClinVar VariationId 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 rank	MANE	Protein	UniProt
ANKH	NM_054027.6	c.*3928C>T		3_prime_UTR_variant	Exon 12 of 12	ENST00000284268.8	NP_473368.1
ANKH	XM_017009644.3	c.*3928C>T		3_prime_UTR_variant	Exon 12 of 12		XP_016865133.1
OTULIN	XM_011514151.3	c.*47-5453G>A		intron_variant	Intron 7 of 7		XP_011512453.1
OTULIN	XR_007058658.1	n.1214-1669G>A		intron_variant	Intron 7 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANKH	ENST00000284268.8	c.*3928C>T		3_prime_UTR_variant	Exon 12 of 12	1	NM_054027.6	ENSP00000284268.6
OTULIN	ENST00000850613.1	c.*47-5453G>A		intron_variant	Intron 7 of 7			ENSP00000520900.1

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

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: 1.00 AC: 2 AN: 2

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AC: 0 AN: 0

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

African (AFR) AF: 0.890 AC: 36230 AN: 40716

American (AMR) AF: 0.911 AC: 13779 AN: 15126

Ashkenazi Jewish (ASJ) AF: 0.905 AC: 3124 AN: 3452

East Asian (EAS) AF: 0.797 AC: 4113 AN: 5160

South Asian (SAS) AF: 0.899 AC: 4311 AN: 4796

European-Finnish (FIN) AF: 0.880 AC: 9005 AN: 10228

Middle Eastern (MID) AF: 0.904 AC: 264 AN: 292

European-Non Finnish (NFE) AF: 0.852 AC: 56592 AN: 66454

Other (OTH) AF: 0.861 AC: 1790 AN: 2080

Alfa AF: 0.931 Hom.: 104330

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Craniometaphyseal dysplasia, autosomal dominant Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		-0.94
Mutation Taster		=12/88	disease causing

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: rs27911; hg19: chr5-14707378;