17-36493971-AAGAC-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_004773.4(ZNHIT3):c.255_258del(p.Asp85GlufsTer7) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000558 in 1,613,774 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000042 (0 hom.)
• Consequence: ZNHIT3 NM_004773.4 frameshift
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.60

Genes affected

ZNHIT3 (HGNC:12309): (zinc finger HIT-type containing 3) Predicted to enable thyroid hormone receptor binding activity. Predicted to be involved in box C/D snoRNP assembly; maturation of LSU-rRNA from tricistronic rRNA transcript (SSU-rRNA, 5.8S rRNA, LSU-rRNA); and snoRNA localization. Located in cytoplasm and nucleus. Implicated in PEHO syndrome. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNHIT3	NM_004773.4	c.255_258del	p.Asp85GlufsTer7	frameshift_variant	4/5	ENST00000617429.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNHIT3	ENST00000617429.5	c.255_258del	p.Asp85GlufsTer7	frameshift_variant	4/5	1	NM_004773.4	P1

Frequencies

GnomAD3 genomes AF: 0.000184 AC: 28 AN: 152250 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000530

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000676 AC: 17 AN: 251372 Hom.: 0 AF XY: 0.0000736 AC XY: 10 AN XY: 135856

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000424 AC: 62 AN: 1461406 Hom.: 0 AF XY: 0.0000454 AC XY: 33 AN XY: 727048

Gnomad4 AFR exome AF: 0.000448

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000306

Gnomad4 OTH exome AF: 0.0000662

GnomAD4 genome AF: 0.000184 AC: 28 AN: 152368 Hom.: 0 Cov.: 33 AF XY: 0.000161 AC XY: 12 AN XY: 74518

Gnomad4 AFR AF: 0.000529

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000356 Hom.: 0

Bravo AF: 0.000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Sep 06, 2023

Variant summary: ZNHIT3 c.255_258delCAGA (p.Asp85GlufsX7) results in a premature termination codon, which is expected to escape nonsense mediated decay. The variant allele was found at a frequency of 6.8e-05 in 251372 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ZNHIT3 causing PEHO Syndrome, allowing no conclusion about variant significance. To our knowledge, no occurrence of c.255_258delCAGA in individuals affected with PEHO Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs529353249; hg19: chr17-34849815;