chr19-33772017-C-T

Position:

chr19-33772017-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_001127895.2(CHST8):c.229C>T(p.Arg77Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0057 in 1,609,794 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0035 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0059 ( 31 hom. )

Consequence

CHST8
NM_001127895.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:3

Conservation

PhyloP100: 0.253

Variant links:

Genes affected

CHST8 (HGNC:15993): (carbohydrate sulfotransferase 8) The protein encoded by this gene belongs to the sulfotransferase 2 family. It is predominantly expressed in the pituitary gland, and is localized to the golgi membrane. This protein catalyzes the transfer of sulfate to position 4 of non-reducing N-acetylgalactosamine (GalNAc) residues in both N-glycans and O-glycans. It is responsible for sulfation of GalNAc on luteinizing hormone (LH), which is required for production of the sex hormones. Mice lacking this enzyme, exhibit increased levels of circulating LH, and precocious sexual maturation of both male and female mice. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Aug 2011]

CHST8 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.013044834).

BP6

Variant 19-33772017-C-T is Benign according to our data. Variant chr19-33772017-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 183645.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2}. Variant chr19-33772017-C-T is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 535 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHST8	NM_001127895.2 linkuse as main transcript	c.229C>T	p.Arg77Trp	missense_variant	5/5	ENST00000650847.1	NP_001121367.1	Q9H2A9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHST8	ENST00000650847.1 linkuse as main transcript	c.229C>T	p.Arg77Trp	missense_variant	5/5		NM_001127895.2	ENSP00000499084.1		Q9H2A9

Frequencies

GnomAD3 genomes

AF:

0.00352

AC:

535

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00109

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00412

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00290

Gnomad FIN

AF:

0.00141

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00569

Gnomad OTH

AF:

0.00430

GnomAD3 exomes

AF:

0.00399

AC:

976

AN:

244402

Hom.:

AF XY:

0.00428

AC XY:

570

AN XY:

133046

show subpopulations

Gnomad AFR exome

AF:

0.00103

Gnomad AMR exome

AF:

0.00210

Gnomad ASJ exome

AF:

0.000103

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00506

Gnomad FIN exome

AF:

0.00299

Gnomad NFE exome

AF:

0.00593

Gnomad OTH exome

AF:

0.00320

GnomAD4 exome

AF:

0.00593

AC:

8638

AN:

1457476

Hom.:

Cov.:

AF XY:

0.00583

AC XY:

4225

AN XY:

724898

show subpopulations

Gnomad4 AFR exome

AF:

0.000931

Gnomad4 AMR exome

AF:

0.00237

Gnomad4 ASJ exome

AF:

0.000116

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00536

Gnomad4 FIN exome

AF:

0.00293

Gnomad4 NFE exome

AF:

0.00680

Gnomad4 OTH exome

AF:

0.00545

GnomAD4 genome

AF:

0.00351

AC:

535

AN:

152318

Hom.:

Cov.:

AF XY:

0.00329

AC XY:

245

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.00108

Gnomad4 AMR

AF:

0.00411

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00290

Gnomad4 FIN

AF:

0.00141

Gnomad4 NFE

AF:

0.00569

Gnomad4 OTH

AF:

0.00425

Alfa

AF:

0.00468

Hom.:

Bravo

AF:

0.00376

TwinsUK

AF:

0.00566

AC:

ALSPAC

AF:

0.00649

AC:

ESP6500AA

AF:

0.000682

AC:

ESP6500EA

AF:

0.00721

AC:

ExAC

AF:

0.00420

AC:

510

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.00687

EpiControl

AF:

0.00587

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 17, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2022	CHST8: BP4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

Peeling skin syndrome type A

Uncertain:2

Uncertain significance, no assertion criteria provided	literature only	OMIM	Apr 01, 2012	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

CHST8-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 28, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Uncertain

-0.060

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.26

.;T;T;T

Eigen

Benign

-0.45

Eigen_PC

Benign

-0.54

FATHMM_MKL

Benign

0.38

LIST_S2

Benign

0.68

T;T;.;.

M_CAP

Uncertain

0.25

MetaRNN

Benign

0.013

T;T;T;T

MetaSVM

Benign

-0.72

MutationAssessor

Benign

0.81

.;L;L;L

PrimateAI

Benign

0.28

PROVEAN

Benign

-1.6

.;N;N;N

REVEL

Uncertain

0.40

Sift

Uncertain

0.0060

.;D;D;D

Sift4G

Uncertain

0.0090

D;D;D;D

Polyphen

0.95

.;P;P;P

Vest4

0.72, 0.70, 0.71

MVP

0.96

MPC

0.93

ClinPred

0.022

GERP RS

4.0

Varity_R

0.070

gMVP

0.45

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