17-36486940-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2 PP5_Very_Strong BP4

The NM_004773.4(ZNHIT3):c.92C>T(p.Ser31Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000197 in 1,611,384 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.00041 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00017 (0 hom.)
• Consequence: ZNHIT3 NM_004773.4 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 4.34

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-36486940-C-T is Pathogenic according to our data. Variant chr17-36486940-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 427725.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-36486940-C-T is described in UniProt as null. Variant chr17-36486940-C-T is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.09791827).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNHIT3	NM_004773.4	c.92C>T	p.Ser31Leu	missense_variant	2/5	ENST00000617429.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNHIT3	ENST00000617429.5	c.92C>T	p.Ser31Leu	missense_variant	2/5	1	NM_004773.4	P1

Frequencies

GnomAD3 genomes AF: 0.000414 AC: 63 AN: 152128 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00528

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000424 AC: 104 AN: 245376 Hom.: 0 AF XY: 0.000434 AC XY: 58 AN XY: 133504

Gnomad AFR exome AF: 0.0000643

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00446

Gnomad NFE exome AF: 0.0000544

Gnomad OTH exome AF: 0.000167

GnomAD4 exome AF: 0.000174 AC: 254 AN: 1459138 Hom.: 0 Cov.: 34 AF XY: 0.000171 AC XY: 124 AN XY: 725930

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: 0.00424

Gnomad4 NFE exome AF: 0.0000153

Gnomad4 OTH exome AF: 0.000232

GnomAD4 genome AF: 0.000414 AC: 63 AN: 152246 Hom.: 0 Cov.: 32 AF XY: 0.000645 AC XY: 48 AN XY: 74436

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00528

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000214 Hom.: 0

Bravo AF: 0.00000378

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000321 AC: 39

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

PEHO syndrome Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	New York Genome Center	Apr 25, 2020	- -
Likely pathogenic, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	May 29, 2020	The heterozygous p.Ser31Leu variant in ZNHIT3 was identified by our study, in the compound heterozygous state, along with another likely pathogenic variant, in an individual with PEHO syndrome (PMID: 31048081). This variant has also been reported in 22 additional individuals with PEHO syndrome, segregated with disease in 4 affected relatives from 2 families (PMID: 28335020), which increases the likelihood that the p.Ser31Leu variant is pathogenic. The variant has also been reported as pathogenic by OMIM in ClinVar (Variation ID: 427725). The p.Ser31Leu variant has been identified in 0.476% (119/25006) of European (Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs148890852). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. The p.Ser31Leu is located in a region of ZNHIT3 that is essential to protein folding and stability, suggesting that this variant is in a functional domain and slightly supports pathogenicity (PMID: 28335020). Additionally, animal models in zebrafish and in vitro functional studies have shown that this variant causes PEHO syndrome (PMID: 28335020). However, these types of experiments may not accurately represent biological function. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PS3, PM3, PM1_Supporting, PP1 (Richards 2015). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Pathogenic	0.37
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.44	T;.
Eigen	Benign	-0.017
Eigen_PC	Benign	-0.070
FATHMM_MKL	Benign	0.55	D
M_CAP	Pathogenic	0.31	D
MetaRNN	Benign	0.098	T;T
MetaSVM	Uncertain	0.24	D
MutationAssessor	Pathogenic	4.0	H;H
MutationTaster	Benign	0.98	D;D;D;D;D
PrimateAI	Uncertain	0.56	T
Sift4G	Uncertain	0.0040	D;D
Polyphen		0.054	B;.
Vest4		0.89
MVP		0.030
ClinPred		0.29	T
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.46
gMVP		0.81

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: rs148890852; hg19: chr17-34842784;