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: 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=-0.89).
• 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.

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.*3928C>T		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.*3928C>T		3_prime_UTR	Exon 12 of 12	ENSP00000284268.6	Q9HCJ1-1
	OTULIN	ENST00000850613.1		c.*47-5453G>A		intron	N/A	ENSP00000520900.1	Q96BN8
	OTULIN	ENST00000921417.1		c.*47-5453G>A		intron	N/A	ENSP00000591476.1

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

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	-0.89
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;