rs149196615

Positions:

chr5-6623222-G-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBS1_SupportingBS2

The NM_017755.6(NSUN2):c.529C>T(p.His177Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00061 in 1,604,466 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00045 ( 0 hom., cov: 30)

Exomes 𝑓: 0.00063 ( 2 hom. )

Consequence

NSUN2
NM_017755.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:1U:7

Conservation

PhyloP100: 7.38

Variant links:

Genes affected

NSUN2 (HGNC:25994): (NOP2/Sun RNA methyltransferase 2) This gene encodes a methyltransferase that catalyzes the methylation of cytosine to 5-methylcytosine (m5C) at position 34 of intron-containing tRNA(Leu)(CAA) precursors. This modification is necessary to stabilize the anticodon-codon pairing and correctly translate the mRNA. Alternatively spliced transcript variants encoding different isoforms have been noted for this gene.[provided by RefSeq, Mar 2011]

NSUN2 links:

NSUN2 (HGNC:):

NSUN2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.15167111).

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000449 (68/151304) while in subpopulation AMR AF= 0.00132 (20/15186). AF 95% confidence interval is 0.000872. There are 0 homozygotes in gnomad4. There are 37 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NSUN2	NM_017755.6 linkuse as main transcript	c.529C>T	p.His177Tyr	missense_variant	5/19	ENST00000264670.11	NP_060225.4	Q08J23-1
NSUN2	NM_001193455.2 linkuse as main transcript	c.424C>T	p.His142Tyr	missense_variant	4/18		NP_001180384.1	Q08J23-2
NSUN2	NR_037947.2 linkuse as main transcript	n.594C>T		non_coding_transcript_exon_variant	5/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
NSUN2	ENST00000264670.11 linkuse as main transcript	c.529C>T	p.His177Tyr	missense_variant	5/19	1	NM_017755.6	ENSP00000264670.6	Q08J23-1
NSUN2	ENST00000506139.5 linkuse as main transcript	c.424C>T	p.His142Tyr	missense_variant	4/18	2		ENSP00000420957.1	Q08J23-2
NSUN2	ENST00000504374.5 linkuse as main transcript	n.529C>T		non_coding_transcript_exon_variant	5/18	2		ENSP00000421783.1	A0A140T9Y7
NSUN2	ENST00000505264.1 linkuse as main transcript	n.139C>T		non_coding_transcript_exon_variant	2/4	4

Frequencies

GnomAD3 genomes

AF:

0.000456

AC:

AN:

151188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000974

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00132

Gnomad ASJ

AF:

0.00116

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000501

Gnomad OTH

AF:

0.000480

GnomAD3 exomes

AF:

0.000516

AC:

126

AN:

244390

Hom.:

AF XY:

0.000591

AC XY:

AN XY:

132012

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000612

Gnomad ASJ exome

AF:

0.00202

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000565

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000589

Gnomad OTH exome

AF:

0.000667

GnomAD4 exome

AF:

0.000627

AC:

911

AN:

1453162

Hom.:

Cov.:

AF XY:

0.000624

AC XY:

451

AN XY:

722656

show subpopulations

Gnomad4 AFR exome

AF:

0.0000609

Gnomad4 AMR exome

AF:

0.000702

Gnomad4 ASJ exome

AF:

0.00193

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000814

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000645

Gnomad4 OTH exome

AF:

0.000716

GnomAD4 genome

AF:

0.000449

AC:

AN:

151304

Hom.:

Cov.:

AF XY:

0.000501

AC XY:

AN XY:

73868

show subpopulations

Gnomad4 AFR

AF:

0.0000971

Gnomad4 AMR

AF:

0.00132

Gnomad4 ASJ

AF:

0.00116

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000501

Gnomad4 OTH

AF:

0.000475

Alfa

AF:

0.000667

Hom.:

Bravo

AF:

0.000650

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.000469

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Intellectual disability, autosomal recessive 5

Pathogenic:1Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Nov 23, 2021	- -
Likely pathogenic, no assertion criteria provided	research	University of Washington Center for Mendelian Genomics, University of Washington	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 13, 2014	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 05, 2022	This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 177 of the NSUN2 protein (p.His177Tyr). This variant is present in population databases (rs149196615, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with NSUN2-related conditions. ClinVar contains an entry for this variant (Variation ID: 129843). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 28, 2023	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified in an individual with Dubowitz syndrome who was also heterozygous for another variant in NSUN2 (Dyment DA et al., 2021); This variant is associated with the following publications: (PMID: 33098347) -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 08, 2021

The c.529C>T (p.H177Y) alteration is located in exon 5 (coding exon 5) of the NSUN2 gene. This alteration results from a C to T substitution at nucleotide position 529, causing the histidine (H) at amino acid position 177 to be replaced by a tyrosine (Y). The p.H177Y alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Intellectual disability

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Jan 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.27

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.24

T;.

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.93

D;D

M_CAP

Benign

0.0089

MetaRNN

Benign

0.15

T;T

MetaSVM

Benign

-0.74

MutationAssessor

Uncertain

2.1

M;.

PrimateAI

Uncertain

0.61

PROVEAN

Uncertain

-3.5

D;D

REVEL

Benign

0.24

Sift

Benign

0.079

T;T

Sift4G

Uncertain

0.056

T;T

Polyphen

0.96

D;.

Vest4

0.65

MVP

0.45

MPC

1.3

ClinPred

0.48

GERP RS

5.3

Varity_R

0.64

gMVP

0.63

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