chr17-36486772-T-G

Position:

• chr17-36486772-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The NM_004773.4(ZNHIT3):​c.73T>G​(p.Cys25Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000138 in 1,450,504 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ZNHIT3 NM_004773.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.71

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 8 ACMG points.

• PM1: In a binding_site (size 0) in uniprot entity ZNHI3_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.978

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNHIT3	NM_004773.4	c.73T>G	p.Cys25Gly	missense_variant	1/5	ENST00000617429.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNHIT3	ENST00000617429.5	c.73T>G	p.Cys25Gly	missense_variant	1/5	1	NM_004773.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1450504 Hom.: 0 Cov.: 39 AF XY: 0.00000139 AC XY: 1 AN XY: 721816

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000516

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 16, 2023

The c.73T>G (p.C25G) alteration is located in exon 1 (coding exon 1) of the ZNHIT3 gene. This alteration results from a T to G substitution at nucleotide position 73, causing the cysteine (C) at amino acid position 25 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	31
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.44	T;.
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Benign	0.50	D
M_CAP	Benign	0.034	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Uncertain	0.68	D
MutationAssessor	Pathogenic	4.1	H;H
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Benign	0.46	T
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.93
MutPred		0.85		Loss of stability (P = 0.0081);Loss of stability (P = 0.0081);
MVP		0.47
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.77
gMVP		0.74

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: chr17-34842616;