Genetic Variant ANKH:c.313+3978G>A (chr5-14764997-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_054027.6(ANKH):c.313+3978G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.416 in 152,120 control chromosomes in the GnomAD database, including 13,330 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 0.42 ( 13330 hom., cov: 33)

Consequence

ANKH
NM_054027.6 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.342

Publications

1 publications found

Variant links:

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

ANKH links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.76).

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.473 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
ANKH	NM_054027.6 link	c.313+3978G>A	intron_variant	Intron 2 of 11	ENST00000284268.8	NP_473368.1	Q9HCJ1-1
ANKH	XM_017009644.3 link	c.229+3978G>A	intron_variant	Intron 2 of 11		XP_016865133.1
ANKH	XM_011514067.2 link	c.313+3978G>A	intron_variant	Intron 2 of 8		XP_011512369.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANKH	ENST00000284268.8 link	c.313+3978G>A		intron_variant	Intron 2 of 11	1	NM_054027.6	ENSP00000284268.6		Q9HCJ1-1

Frequencies

GnomAD3 genomes

AF:

0.416

AC:

63288

AN:

152002

Hom.:

13314

Cov.:

show subpopulations

Gnomad AFR

AF:

0.458

Gnomad AMI

AF:

0.377

Gnomad AMR

AF:

0.482

Gnomad ASJ

AF:

0.330

Gnomad EAS

AF:

0.379

Gnomad SAS

AF:

0.318

Gnomad FIN

AF:

0.468

Gnomad MID

AF:

0.250

Gnomad NFE

AF:

0.386

Gnomad OTH

AF:

0.362

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

GnomAD4 genome

AF:

0.416

AC:

63345

AN:

152120

Hom.:

13330

Cov.:

AF XY:

0.417

AC XY:

31039

AN XY:

74356

show subpopulations

African (AFR)

AF:

0.458

AC:

18990

AN:

41486

American (AMR)

AF:

0.482

AC:

7365

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.330

AC:

1145

AN:

3470

East Asian (EAS)

AF:

0.379

AC:

1963

AN:

5176

South Asian (SAS)

AF:

0.319

AC:

1538

AN:

4826

European-Finnish (FIN)

AF:

0.468

AC:

4937

AN:

10560

Middle Eastern (MID)

AF:

0.235

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.386

AC:

26238

AN:

67996

Other (OTH)

AF:

0.358

AC:

756

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1940

3879

5819

7758

9698

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

598

1196

1794

2392

2990

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.417

Hom.:

2253

Bravo

AF:

0.417

Asia WGS

AF:

0.351

AC:

1220

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.76

CADD

Benign

6.1

(source)

DANN

Benign

0.90

PhyloP100

0.34

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over