rs201228623

Variant names:

• chr17-36486954-C-T
• rs201228623
• NM_004773.4:c.106C>T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_004773.4(ZNHIT3):​c.106C>T​(p.Arg36Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000267 in 1,611,466 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R36L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: ZNHIT3 NM_004773.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.577
• Publications: 0 publications found

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]

ZNHIT3 Gene-Disease associations (from GenCC):

• PEHO syndrome

  Inheritance: AR, AD Classification: MODERATE, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
• Mayer-Rokitansky-Kuster-Hauser syndrome

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ENSG00000289011 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.4084453).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004773.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNHIT3	NM_004773.4	MANE Select	c.106C>T	p.Arg36Trp	missense	Exon 2 of 5	NP_004764.1	Q15649-1
	ZNHIT3	NM_001281432.2		c.106C>T	p.Arg36Trp	missense	Exon 2 of 5	NP_001268361.1	Q15649-2
	ZNHIT3	NM_001281434.2		c.106C>T	p.Arg36Trp	missense	Exon 2 of 3	NP_001268363.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNHIT3	ENST00000617429.5	TSL:1 MANE Select	c.106C>T	p.Arg36Trp	missense	Exon 2 of 5	ENSP00000484687.1	Q15649-1
	ZNHIT3	ENST00000619730.4	TSL:1	c.-222+169C>T		intron	N/A	ENSP00000481499.1	A0A087WY42
	ZNHIT3	ENST00000612728.4	TSL:1	n.108+169C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152144 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000387

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000203 AC: 5 AN: 245830 AF XY: 0.0000224

Gnomad AFR exome AF: 0.000192

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000112

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000164 AC: 24 AN: 1459204 Hom.: 0 Cov.: 34 AF XY: 0.0000152 AC XY: 11 AN XY: 725988

African (AFR) AF: 0.000240 AC: 8 AN: 33282

American (AMR) AF: 0.00 AC: 0 AN: 44332

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26072

East Asian (EAS) AF: 0.000331 AC: 13 AN: 39306

South Asian (SAS) AF: 0.00 AC: 0 AN: 86026

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52640

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111516

Other (OTH) AF: 0.00 AC: 0 AN: 60276

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152262 Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13 AN XY: 74448

African (AFR) AF: 0.000409 AC: 17 AN: 41556

American (AMR) AF: 0.00 AC: 0 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000388 AC: 2 AN: 5160

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68008

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000151

ExAC AF: 0.0000495 AC: 6

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	T
Eigen	Uncertain	0.21
Eigen_PC	Benign	0.12
FATHMM_MKL	Benign	0.54	D
M_CAP	Uncertain	0.096	D
MetaRNN	Benign	0.41	T
MetaSVM	Benign	-0.75	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		0.58
PrimateAI	Benign	0.25	T
Sift4G	Uncertain	0.0020	D
Polyphen		0.94	P
Vest4		0.59
MVP		0.14
ClinPred		0.36	T
GERP RS		2.5
PromoterAI		-0.44	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.24
gMVP		0.67
Mutation Taster		=82/18	polymorphism

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

Other links and lift over

dbSNP: rs201228623; hg19: chr17-34842798;