5-14871451-C-T

Variant names:

• chr5-14871451-C-T
• rs78431233
• NM_054027.6:c.-4G>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_054027.6(ANKH):​c.-4G>A variant causes a 5 prime UTR change. The variant allele was found at a frequency of 0.0684 in 1,610,634 control chromosomes in the GnomAD database, including 4,327 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.053 (334 hom., cov: 32)
  • Exomes 𝑓: 0.070 (3993 hom.)
• Consequence: ANKH NM_054027.6 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 3.72
• Publications: 11 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 5-14871451-C-T is Benign according to our data. Variant chr5-14871451-C-T is described in ClinVar as Benign. ClinVar VariationId is 351926.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0817 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.-4G>A		5_prime_UTR	Exon 1 of 12	NP_473368.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANKH	ENST00000284268.8	TSL:1 MANE Select	c.-4G>A		5_prime_UTR	Exon 1 of 12	ENSP00000284268.6
	ANKH	ENST00000887636.1		c.-4G>A		5_prime_UTR	Exon 1 of 12	ENSP00000557695.1
	ANKH	ENST00000964374.1		c.-4G>A		5_prime_UTR	Exon 1 of 12	ENSP00000634433.1

Frequencies

GnomAD3 genomes AF: 0.0529 AC: 8041 AN: 151890 Hom.: 334 Cov.: 32

Gnomad AFR AF: 0.0138

Gnomad AMI AF: 0.134

Gnomad AMR AF: 0.0360

Gnomad ASJ AF: 0.0374

Gnomad EAS AF: 0.000195

Gnomad SAS AF: 0.0226

Gnomad FIN AF: 0.0708

Gnomad MID AF: 0.0865

Gnomad NFE AF: 0.0835

Gnomad OTH AF: 0.0527

GnomAD2 exomes AF: 0.0544 AC: 13441 AN: 247074 AF XY: 0.0563

Gnomad AFR exome AF: 0.0120

Gnomad AMR exome AF: 0.0276

Gnomad ASJ exome AF: 0.0390

Gnomad EAS exome AF: 0.000110

Gnomad FIN exome AF: 0.0761

Gnomad NFE exome AF: 0.0823

Gnomad OTH exome AF: 0.0562

GnomAD4 exome AF: 0.0700 AC: 102171 AN: 1458632 Hom.: 3993 Cov.: 31 AF XY: 0.0695 AC XY: 50463 AN XY: 725692

African (AFR) AF: 0.0112 AC: 373 AN: 33416

American (AMR) AF: 0.0294 AC: 1314 AN: 44650

Ashkenazi Jewish (ASJ) AF: 0.0403 AC: 1051 AN: 26072

East Asian (EAS) AF: 0.000177 AC: 7 AN: 39640

South Asian (SAS) AF: 0.0287 AC: 2474 AN: 86186

European-Finnish (FIN) AF: 0.0779 AC: 4116 AN: 52840

Middle Eastern (MID) AF: 0.0769 AC: 437 AN: 5680

European-Non Finnish (NFE) AF: 0.0798 AC: 88601 AN: 1109970

Other (OTH) AF: 0.0631 AC: 3798 AN: 60178

GnomAD4 genome AF: 0.0529 AC: 8036 AN: 152002 Hom.: 334 Cov.: 32 AF XY: 0.0508 AC XY: 3775 AN XY: 74306

African (AFR) AF: 0.0138 AC: 572 AN: 41500

American (AMR) AF: 0.0359 AC: 548 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0374 AC: 130 AN: 3472

East Asian (EAS) AF: 0.000195 AC: 1 AN: 5118

South Asian (SAS) AF: 0.0222 AC: 107 AN: 4814

European-Finnish (FIN) AF: 0.0708 AC: 748 AN: 10558

Middle Eastern (MID) AF: 0.0788 AC: 23 AN: 292

European-Non Finnish (NFE) AF: 0.0835 AC: 5675 AN: 67944

Other (OTH) AF: 0.0521 AC: 110 AN: 2110

Alfa AF: 0.0572 Hom.: 157

Bravo AF: 0.0472

Asia WGS AF: 0.0100 AC: 35 AN: 3478

EpiCase AF: 0.0800

EpiControl AF: 0.0811

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Craniometaphyseal dysplasia, autosomal dominant (2)
-	-	1	Chondrocalcinosis 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	22
DANN	Benign	0.74
PhyloP100		3.7
PromoterAI		-0.082	Neutral
Mutation Taster		=299/1	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: rs78431233; hg19: chr5-14871560;