4-120695217-TTA-T

Variant summary

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

The NM_018699.4(PRDM5):c.1785_1786del(p.His595GlnfsTer14) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,340 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: PRDM5 NM_018699.4 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.53

Genes affected

PRDM5 (HGNC:9349): (PR/SET domain 5) The protein encoded by this gene is a transcription factor of the PR-domain protein family. It contains a PR-domain and multiple zinc finger motifs. Transcription factors of the PR-domain family are known to be involved in cell differentiation and tumorigenesis. [provided by RefSeq, Jul 2008]

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 0.0571 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 4-120695217-TTA-T is Pathogenic according to our data. Variant chr4-120695217-TTA-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1683364.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRDM5	NM_018699.4	c.1785_1786del	p.His595GlnfsTer14	frameshift_variant	16/16	ENST00000264808.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRDM5	ENST00000264808.8	c.1785_1786del	p.His595GlnfsTer14	frameshift_variant	16/16	1	NM_018699.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461340 Hom.: 0 AF XY: 0.00000688 AC XY: 5 AN XY: 726960

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: 0.00000630

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Brittle cornea syndrome 2 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Apr 20, 2022

Variant summary: PRDM5 c.1785_1786delTA (p.His595GlnfsX14) results in a premature termination codon within the last exon, predicted to cause a truncation of the encoded protein, which is a commonly known mechanism for disease. This truncation is expected to abolish the last 22 amino acids and eliminate the majority of the most C-terminal zinc finger domain of the protein. The variant was absent in 250858 control chromosomes (gnomAD). To our knowledge, no occurrence of c.1785_1786delTA in individuals affected with Brittle Cornea Syndrome 2 and no experimental evidence demonstrating its impact on protein function have been reported. Nevertheless, other truncations within the last exon of PRDM5 have been reported in patients affected with Brittle Cornea Syndrome. Specifically, a truncation upstream of the variant (c.1768C>T, p.Arg590X) was reported in multiple homozygous affected individuals from one family (PMID: 21664999), while a truncation downstream of the variant (c.1858delC, p.His620ThrfsX8) has also been reported in one homozygous affected individual (PMID: 33739556). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1734381962; hg19: chr4-121616372;