11-45934054-CA-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_001352027.3(PHF21A):c.1959del(p.Ala654ProfsTer103) 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 Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PHF21A NM_001352027.3 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.03

Genes affected

PHF21A (HGNC:24156): (PHD finger protein 21A) The PHF21A gene encodes BHC80, a component of a BRAF35 (MIM 605535)/histone deacetylase (HDAC; see MIM 601241) complex (BHC) that mediates repression of neuron-specific genes through the cis-regulatory element known as repressor element-1 (RE1) or neural restrictive silencer (NRS) (Hakimi et al., 2002 [PubMed 12032298]).[supplied by OMIM, Nov 2010]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0425 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-45934054-CA-C is Pathogenic according to our data. Variant chr11-45934054-CA-C is described in ClinVar as [Pathogenic]. Clinvar id is 1917917.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PHF21A	NM_001352027.3	c.1959del	p.Ala654ProfsTer103	frameshift_variant	19/19	ENST00000676320.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PHF21A	ENST00000676320.1	c.1959del	p.Ala654ProfsTer103	frameshift_variant	19/19		NM_001352027.3	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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

Invitae

Aug 23, 2023

This sequence change results in a frameshift in the PHF21A gene (p.Ala653Profs*103). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 28 amino acid(s) of the PHF21A protein and extend the protein by 74 additional amino acid residues. This variant is not present in population databases (gnomAD no frequency). This frameshift has been observed in individual(s) with PHF21A-related conditions (PMID: 31649809). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 1917917). For these reasons, this variant has been classified as 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: chr11-45955605;