Genetic Variant ZNHIT6:p.Arg396His (chr1-85677296-C-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_017953.4(ZNHIT6):c.1187G>A(p.Arg396His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000667 in 1,605,098 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict 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. R396C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00035 ( 2 hom., cov: 33)

Exomes 𝑓: 0.000037 ( 0 hom. )

Consequence

ZNHIT6
NM_017953.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.617

Variant links:

Genes affected

ZNHIT6 (HGNC:26089): (zinc finger HIT-type containing 6) Enables ATPase binding activity; TFIID-class transcription factor complex binding activity; and identical protein binding activity. Involved in box C/D snoRNP assembly; protein complex oligomerization; and snoRNA localization. Located in extracellular exosome. Part of pre-snoRNP complex. [provided by Alliance of Genome Resources, Apr 2022]

ZNHIT6 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.01689437).

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNHIT6	NM_017953.4 link	c.1187G>A	p.Arg396His	missense_variant	Exon 8 of 10	ENST00000370574.4	NP_060423.3	Q9NWK9-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNHIT6	ENST00000370574.4 link	c.1187G>A	p.Arg396His	missense_variant	Exon 8 of 10	1	NM_017953.4	ENSP00000359606.3		Q9NWK9-1
ZNHIT6	ENST00000431532.6 link	c.1070G>A	p.Arg357His	missense_variant	Exon 9 of 11	2		ENSP00000414344.2		Q9NWK9-2

Frequencies

GnomAD3 genomes

AF:

0.000349

AC:

AN:

151920

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00335

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000135

AC:

AN:

243990

Hom.:

AF XY:

0.000114

AC XY:

AN XY:

131846

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000551

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000389

Gnomad SAS exome

AF:

0.0000708

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000358

Gnomad OTH exome

AF:

0.000337

GnomAD4 exome

AF:

0.0000372

AC:

AN:

1453178

Hom.:

Cov.:

AF XY:

0.0000360

AC XY:

AN XY:

722624

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000421

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000279

Gnomad4 SAS exome

AF:

0.0000239

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000171

Gnomad4 OTH exome

AF:

0.0000666

GnomAD4 genome

AF:

0.000349

AC:

AN:

151920

Hom.:

Cov.:

AF XY:

0.000458

AC XY:

AN XY:

74198

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.00335

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000901

Hom.:

Bravo

AF:

0.000253

ExAC

AF:

0.0000494

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 10, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1187G>A (p.R396H) alteration is located in exon 8 (coding exon 8) of the ZNHIT6 gene. This alteration results from a G to A substitution at nucleotide position 1187, causing the arginine (R) at amino acid position 396 to be replaced by a histidine (H). 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

Benign

0.065

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.73

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.021

.;T

Eigen

Benign

-0.76

Eigen_PC

Benign

-0.69

FATHMM_MKL

Benign

0.020

LIST_S2

Benign

0.65

T;T

M_CAP

Benign

0.0067

MetaRNN

Benign

0.017

T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.55

.;N

PrimateAI

Benign

0.21

PROVEAN

Benign

-0.59

N;N

REVEL

Benign

0.049

Sift

Benign

0.26

T;T

Sift4G

Benign

0.64

T;T

Polyphen

0.0080

.;B

Vest4

0.072

MutPred

0.42

.;Loss of MoRF binding (P = 0.0144);

MVP

0.18

MPC

0.21

ClinPred

0.053

GERP RS

-1.3

Varity_R

0.025

gMVP

0.13

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over