rs777736953

chr1-27549343-G-Achr1-27549343-G-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_001371928.1(AHDC1):c.2773C>T(p.Arg925Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R925R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: AHDC1 NM_001371928.1 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5 O:1
• Conservation: PhyloP100: 0.939

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]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 32 pathogenic variants in the truncated region.
• PP5: Variant 1-27549343-G-A is Pathogenic according to our data. Variant chr1-27549343-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 496678.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AHDC1	NM_001371928.1	c.2773C>T	p.Arg925Ter	stop_gained	8/9	ENST00000673934.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AHDC1	ENST00000673934.1	c.2773C>T	p.Arg925Ter	stop_gained	8/9		NM_001371928.1	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1459490 Hom.: 0 Cov.: 105 AF XY: 0.00 AC XY: 0 AN XY: 725960

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

AHDC1-related intellectual disability - obstructive sleep apnea - mild dysmorphism syndrome Pathogenic:2 Other:1

Pathogenic, no assertion criteria provided	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 20, 2020	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -
not provided, no classification provided	literature only	GeneReviews	-	Recurring pathogenic variant -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 28, 2019	Observed de novo without confirmed parentage in multiple unrelated patients with features of Xia-Gibbs syndrome in published literature (Jiang et al., 2018); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016) -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -

Abdominal obesity-metabolic syndrome 3 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Mar 31, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.54
Cadd	Pathogenic	38
Dann	Uncertain	1.0
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.92	D
MutationTaster	Benign	1.0	A;A
Vest4		0.30
GERP RS		3.2

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

LitVar

Other links and lift over

dbSNP: rs777736953; hg19: chr1-27875854; COSMIC: COSV55942294; COSMIC: COSV55942294;