chr5-14742877-A-G

Variant names:

• chr5-14742877-A-G
• rs153930
• NM_054027.6:c.916-955T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_054027.6(ANKH):​c.916-955T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.303 in 152,160 control chromosomes in the GnomAD database, including 8,194 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.30 (8194 hom., cov: 33)
• Consequence: ANKH NM_054027.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.00
• Publications: 2 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, Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp
• craniometaphyseal dysplasia, autosomal dominant

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

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.497 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANKH	NM_054027.6	MANE Select	c.916-955T>C		intron	N/A	NP_473368.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANKH	ENST00000284268.8	TSL:1 MANE Select	c.916-955T>C		intron	N/A	ENSP00000284268.6
	ANKH	ENST00000503939.5	TSL:3	n.428-955T>C		intron	N/A
	ANKH	ENST00000515517.1	TSL:3	n.150-955T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.302 AC: 45980 AN: 152042 Hom.: 8178 Cov.: 33

Gnomad AFR AF: 0.503

Gnomad AMI AF: 0.258

Gnomad AMR AF: 0.280

Gnomad ASJ AF: 0.162

Gnomad EAS AF: 0.132

Gnomad SAS AF: 0.0883

Gnomad FIN AF: 0.236

Gnomad MID AF: 0.204

Gnomad NFE AF: 0.232

Gnomad OTH AF: 0.295

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.303 AC: 46039 AN: 152160 Hom.: 8194 Cov.: 33 AF XY: 0.297 AC XY: 22075 AN XY: 74392

African (AFR) AF: 0.503 AC: 20867 AN: 41510

American (AMR) AF: 0.280 AC: 4278 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.162 AC: 562 AN: 3464

East Asian (EAS) AF: 0.132 AC: 684 AN: 5180

South Asian (SAS) AF: 0.0880 AC: 424 AN: 4820

European-Finnish (FIN) AF: 0.236 AC: 2506 AN: 10602

Middle Eastern (MID) AF: 0.209 AC: 61 AN: 292

European-Non Finnish (NFE) AF: 0.232 AC: 15805 AN: 67990

Other (OTH) AF: 0.292 AC: 617 AN: 2114

Alfa AF: 0.144 Hom.: 274

Bravo AF: 0.320

Asia WGS AF: 0.144 AC: 504 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.58
DANN	Benign	0.48
PhyloP100		-1.0
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: rs153930; hg19: chr5-14742986;