NM_054027.6:c.1165G>T

Variant names:

• chr5-14713644-C-A
• rs28939080
• NM_054027.6:c.1165G>T
• ANKH p.Gly389Trp

GermlineCancer (beta)

Variant summary

Our verdict is Likely pathogenic.

+6 Likely Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 6 classification points (ACMG Germline Pathogenicity v2019). PM2PM5PP3_Moderate

The NM_054027.6(ANKH):c.1165G>T (p.Gly389Trp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a cumulative frequency of 0.00000137 (AC=2) in the gnomAD database across 1,461,808 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000003. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 7.90). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. A different missense at the same amino acid position has been reported as Pathogenic/Likely Pathogenic in ClinVar: p.G389R: Likely_pathogenic (ClinVar VariationId 5192, 1 star) Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.G389= (synonymous): Benign (ClinVar VariationId 1166706, 1 star)

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ANKH NM_054027.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.90
• Publications: 0 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]

ANKH Gene-Disease associations (from GenCC):

• chondrocalcinosis 2

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae), PanelApp Australia
• craniometaphyseal dysplasia, autosomal dominant

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), PanelApp Australia
• skeletal dysplasia

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• craniometaphyseal dysplasia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

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: PanelApp Australia, Orphanet, Labcorp Genetics (formerly Invitae), G2P, ClinGen, Ambry Genetics
• autoinflammation, panniculitis, and dermatosis syndrome, autosomal dominant

  Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia
• 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

LOC100130744 (HGNC:):

Classification according to ACMG Germline Pathogenicity v2019

Our verdict: Likely_pathogenic. The variant received 6 points.

• PM2: Very rare in gnomAD for AD/XL gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.0000003 — very rare for AD/XL gene (threshold 0.0001) — PM2 moderate.
• PM5: Different pathogenic missense at same AA residue in ClinVar (PM5); ClinVar contains a germline Pathogenic/Likely Pathogenic entry at the same amino acid position with a different amino acid change: p.G389R: Likely_pathogenic (ClinVar VariationId 5192, 1 star); Other variants at the same amino acid residue (not pathogenic): p.G389= (synonymous): Benign (ClinVar VariationId 1166706, 1 star)
• PP3: Germline meta computational scorer (REVEL/MetaRNN/BayesDel) predicts damaging effect — moderate evidence (PP3); Splicing verdict: not pathogenic.; Germline computational verdict: pathogenic (Moderate).

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANKH	NM_054027.6	MANE Select	c.1165G>T	p.Gly389Trp	missense	Exon 10 of 12	NP_473368.1	Q9HCJ1-1
	LOC100130744	NR_046285.1		n.951C>A		non_coding_transcript_exon	Exon 1 of 2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANKH	ENST00000284268.8	TSL:1 MANE Select	c.1165G>T	p.Gly389Trp	missense	Exon 10 of 12	ENSP00000284268.6	Q9HCJ1-1
	ANKH	ENST00000887636.1		c.1165G>T	p.Gly389Trp	missense	Exon 10 of 12	ENSP00000557695.1
	ANKH	ENST00000964374.1		c.1159G>T	p.Gly387Trp	missense	Exon 10 of 12	ENSP00000634433.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461808 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727206

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5712

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1112008

Other (OTH) AF: 0.00 AC: 0 AN: 60378

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.74	D
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.60	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	0.97	L
PhyloP100		7.9
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-4.4	D
REVEL	Pathogenic	0.83
Sift	Uncertain	0.012	D
Sift4G	Uncertain	0.0020	D
Varity_R		0.58
gMVP		0.99
Mutation Taster		=26/74	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs28939080;

hg19: chr5-14713753;

COSMIC: COSV105876656;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar