rs1165205177

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_001371928.1(AHDC1):c.2062C>T(p.Arg688*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,452,868 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

AHDC1
NM_001371928.1 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 2.62

Publications

3 publications found

Variant links:

Genes affected

AHDC1 (HGNC:25230): (AT-hook DNA binding motif containing 1) This gene encodes a protein containing two AT-hooks, which likely function in DNA binding. Mutations in this gene were found in individuals with Xia-Gibbs syndrome. [provided by RefSeq, Jun 2014]

AHDC1 Gene-Disease associations (from GenCC):

AHDC1-related intellectual disability - obstructive sleep apnea - mild dysmorphism syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Illumina, Orphanet, G2P, ClinGen

AHDC1 links:

ENSG00000300470 (HGNC:):

ENSG00000300470 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 1-27550054-G-A is Pathogenic according to our data. Variant chr1-27550054-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 438276.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AHDC1	NM_001371928.1 link	c.2062C>T	p.Arg688*	stop_gained	Exon 8 of 9	ENST00000673934.1	NP_001358857.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AHDC1	ENST00000673934.1 link	c.2062C>T	p.Arg688*	stop_gained	Exon 8 of 9		NM_001371928.1	ENSP00000501218.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.88e-7

AC:

AN:

1452868

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

721544

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33312

American (AMR)

AF:

0.00

AC:

AN:

44300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25890

East Asian (EAS)

AF:

0.00

AC:

AN:

39484

South Asian (SAS)

AF:

0.00

AC:

AN:

85850

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51694

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5732

European-Non Finnish (NFE)

AF:

9.04e-7

AC:

AN:

1106676

Other (OTH)

AF:

0.00

AC:

AN:

59930

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

AHDC1-related intellectual disability - obstructive sleep apnea - mild dysmorphism syndrome

Pathogenic:5

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 23, 2016

Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 01, 2016

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 13, 2021

Pediatric Genetics Clinic, Sheba Medical Center

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Pathogenic:2

Aug 04, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 438276). This premature translational stop signal has been observed in individual(s) with Xia-Gibbs syndrome (PMID: 29696776). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg688*) in the AHDC1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in AHDC1 are known to be pathogenic (PMID: 24791903, 27148574). -

Jun 30, 2023

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nonsense variant predicted to result in protein truncation in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30729726, 37216737, 29696776, 33644933, 35599849, 34580403) -

Intellectual disability

Pathogenic:1

Aug 08, 2019

Cambridge Genomics Laboratory, East Genomic Laboratory Hub, NHS Genomic Medicine Service

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.59

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

0.72

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Uncertain

0.94

PhyloP100

2.6

Vest4

0.36

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=1/199

disease causing (ClinVar)

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over