rs796065043

Positions:

• chr1-27549570-GAGTCATCCGAATCGAGC-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001371928.1(AHDC1):​c.2529_2545del​(p.Asp845ArgfsTer40) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: AHDC1 NM_001371928.1 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.42

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 12 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 34 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-27549570-GAGTCATCCGAATCGAGC-G is Pathogenic according to our data. Variant chr1-27549570-GAGTCATCCGAATCGAGC-G is described in ClinVar as [Pathogenic]. Clinvar id is 208159.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AHDC1	NM_001371928.1	c.2529_2545del	p.Asp845ArgfsTer40	frameshift_variant	8/9	ENST00000673934.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AHDC1	ENST00000673934.1	c.2529_2545del	p.Asp845ArgfsTer40	frameshift_variant	8/9		NM_001371928.1	P1

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 07, 2015

c.2529_2545delGCTCGATTCGGATGACT: p.Asp845ArgfsX40 in exon 6 in the AHDC1 gene (NM_001029882.2). The normal sequence with the number of bases that are deleted in braces is: CGCT{GCTCGATTCGGATGACT}CCTC. The c.2529_2545delGCTCGATTCGGATGACT variant in the AHDC1 gene has not been reported previously as a disease-causing mutation nor as a benign polymorphism, to our knowledge. The c.2529_2545delGCTCGATTCGGATGACT variant causes a frameshift starting with codon Asparagine 845, changes this amino acid to an Arginine residue and creates a premature Stop codon at position 40 of the new reading frame, denoted p.Asp845ArgfsX40. This variant is predicted to cause loss of normal protein function through protein truncation; it causes the deletion of the last 759 amino acids and an insertion of 39 incorrect amino acids. The c.2529_2545delGCTCGATTCGGATGACT variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Protein truncating variants downstream of this variant have been reported in association with Xia-Gibbs syndrome (Xia et al., 2014), supporting the pathogenicity of more upstream truncating variants. We interpret c.2529_2545delGCTCGATTCGGATGACT as a pathogenic variant. This variant has been observed to be de novo with confirmed parentage. This variant was found in AHDC1 panel(s). -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs796065043; hg19: chr1-27876081;