chr6-117693132-C-G

Position:

chr6-117693132-C-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_138459.5(NUS1):c.506C>G(p.Pro169Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0016 in 1,612,386 control chromosomes in the GnomAD database, including 7 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0017 ( 7 hom. )

Consequence

NUS1
NM_138459.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: 1.83

Variant links:

Genes affected

NUS1 (HGNC:21042): (NUS1 dehydrodolichyl diphosphate synthase subunit) This gene encodes a type I single transmembrane domain receptor, which is a subunit of cis-prenyltransferase, and serves as a specific receptor for the neural and cardiovascular regulator Nogo-B. The encoded protein is essential for dolichol synthesis and protein glycosylation. This gene is highly expressed in non-small cell lung carcinomas as well as estrogen receptor-alpha positive breast cancer cells where it promotes epithelial mesenchymal transition. This gene is associated with the poor prognosis of human hepatocellular carcinoma patients. Naturally occurring mutations in this gene cause a congenital disorder of glycosylation and are associated with epilepsy. A knockout of the orthologous gene in mice causes embryonic lethality before day 6.5. Pseudogenes of this gene have been defined on chromosomes 13 and X. [provided by RefSeq, May 2017]

NUS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008862853).

BP6

Variant 6-117693132-C-G is Benign according to our data. Variant chr6-117693132-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 569348.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00112 (170/152020) while in subpopulation NFE AF= 0.00177 (120/67900). AF 95% confidence interval is 0.00151. There are 0 homozygotes in gnomad4. There are 83 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 7 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NUS1	NM_138459.5 linkuse as main transcript	c.506C>G	p.Pro169Arg	missense_variant	2/5	ENST00000368494.4	NP_612468.1	Q96E22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NUS1	ENST00000368494.4 linkuse as main transcript	c.506C>G	p.Pro169Arg	missense_variant	2/5	1	NM_138459.5	ENSP00000357480.3		Q96E22

Frequencies

GnomAD3 genomes

AF:

0.00112

AC:

170

AN:

151902

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000314

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00105

Gnomad ASJ

AF:

0.000289

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.00123

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00177

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.00137

AC:

344

AN:

250502

Hom.:

AF XY:

0.00151

AC XY:

204

AN XY:

135436

show subpopulations

Gnomad AFR exome

AF:

0.000124

Gnomad AMR exome

AF:

0.000843

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000623

Gnomad FIN exome

AF:

0.000924

Gnomad NFE exome

AF:

0.00238

Gnomad OTH exome

AF:

0.000655

GnomAD4 exome

AF:

0.00165

AC:

2410

AN:

1460366

Hom.:

Cov.:

AF XY:

0.00163

AC XY:

1184

AN XY:

726578

show subpopulations

Gnomad4 AFR exome

AF:

0.000299

Gnomad4 AMR exome

AF:

0.00101

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000720

Gnomad4 FIN exome

AF:

0.000992

Gnomad4 NFE exome

AF:

0.00194

Gnomad4 OTH exome

AF:

0.00139

GnomAD4 genome

AF:

0.00112

AC:

170

AN:

152020

Hom.:

Cov.:

AF XY:

0.00112

AC XY:

AN XY:

74310

show subpopulations

Gnomad4 AFR

AF:

0.000313

Gnomad4 AMR

AF:

0.00105

Gnomad4 ASJ

AF:

0.000289

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000623

Gnomad4 FIN

AF:

0.00123

Gnomad4 NFE

AF:

0.00177

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00174

Hom.:

Bravo

AF:

0.00131

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00175

AC:

ExAC

AF:

0.00155

AC:

188

EpiCase

AF:

0.00202

EpiControl

AF:

0.00202

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Intellectual disability, autosomal dominant 55, with seizures

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 04, 2018

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

NUS1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 01, 2023

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). -

Congenital disorder of glycosylation, type IAA

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 27, 2024

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jun 01, 2024

NUS1: BP4 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.54

CADD

Benign

DANN

Benign

0.91

DEOGEN2

Benign

0.053

Eigen

Benign

-0.19

Eigen_PC

Benign

-0.057

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.84

M_CAP

Benign

0.0073

MetaRNN

Benign

0.0089

MetaSVM

Benign

-0.97

MutationAssessor

Benign

1.2

PrimateAI

Benign

0.35

PROVEAN

Benign

-2.3

REVEL

Benign

0.025

Sift

Benign

0.35

Sift4G

Benign

0.25

Polyphen

0.14

Vest4

0.23

MVP

0.093

MPC

0.60

ClinPred

0.017

GERP RS

3.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.082

gMVP

0.36

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