NM_032217.5:c.7430delC

Variant names:

• chr4-73077511-AG-A
• NM_032217.5:c.7430delC

Variant summary

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

The NM_032217.5(ANKRD17):​c.7430delC​(p.Pro2477LeufsTer7) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ANKRD17 NM_032217.5 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.38

Genes affected

ANKRD17 (HGNC:23575): (ankyrin repeat domain 17) The protein encoded by this gene belongs to the family of ankyrin repeat-containing proteins, and contains two distinct arrays of ankyrin repeats in its amino-terminal region, one with 15 ankyrin repeats, and the other with 10 ankyrin repeats. It also contains a nuclear export signal, nuclear localization signal, and a cyclin-binding RXL motif. Localization of this protein to the nucleus has been shown experimentally, and interactions between this protein and cyclin-dependent kinase 2 have been observed. It has been suggested that this protein plays a role in both DNA replication and in both anti-viral and anti-bacterial innate immune pathways. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Dec 2015]

ACMG classification

Verdict is Pathogenic. Variant got 12 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 4-73077511-AG-A is Pathogenic according to our data. Variant chr4-73077511-AG-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3600515.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANKRD17	NM_032217.5	c.7430delC	p.Pro2477LeufsTer7	frameshift_variant	Exon 32 of 34	ENST00000358602.9	NP_115593.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANKRD17	ENST00000358602.9	c.7430delC	p.Pro2477LeufsTer7	frameshift_variant	Exon 32 of 34	5	NM_032217.5	ENSP00000351416.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Chopra-Amiel-Gordon syndrome Pathogenic:1

Oct 07, 2024

Clinical Genomics Laboratory, Washington University in St. Louis

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The ANKRD17 c.7430del (p.Pro2477Leufs*7) variant, to our knowledge, has not been reported in the medical literature. This variant is absent from the general population (gnomAD v.2.1.1), indicating it is not a common variant. This variant causes a frameshift by deleting one nucleotide, leading to a premature termination codon, which is predicted to lead to nonsense mediated decay. Variants introducing a premature termination codon in this region have been described in affected individuals and are considered pathogenic (ClinVar ID: 3254702; Chopra M et al., PMID: 33909992). Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-73943228;