rs773527127

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1PP3_Moderate

The NM_032193.4(RNASEH2C):c.115G>T(p.Asp39Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000493 in 1,419,906 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. D39N) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000049 ( 0 hom. )

Consequence

RNASEH2C
NM_032193.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.257

Publications

3 publications found

Variant links:

Genes affected

RNASEH2C (HGNC:24116): (ribonuclease H2 subunit C) This gene encodes a ribonuclease H subunit that can cleave ribonucleotides from RNA:DNA duplexes. Mutations in this gene cause Aicardi-Goutieres syndrome-3, a disease that causes severe neurologic dysfunction. A pseudogene for this gene has been identified on chromosome Y, near the sex determining region Y (SRY) gene. [provided by RefSeq, Jul 2008]

RNASEH2C Gene-Disease associations (from GenCC):

Aicardi-Goutieres syndrome 3
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia
Aicardi-Goutieres syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

RNASEH2C links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM1

In a chain Ribonuclease H2 subunit C (size 163) in uniprot entity RNH2C_HUMAN there are 7 pathogenic changes around while only 2 benign (78%) in NM_032193.4

PP3

MetaRNN computational evidence supports a deleterious effect, 0.899

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RNASEH2C	NM_032193.4 link	c.115G>T	p.Asp39Tyr	missense_variant	Exon 1 of 4	ENST00000308418.10	NP_115569.2	Q8TDP1A0A024R5B3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RNASEH2C	ENST00000308418.10 link	c.115G>T	p.Asp39Tyr	missense_variant	Exon 1 of 4	1	NM_032193.4	ENSP00000308193.5		Q8TDP1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000109

AC:

AN:

182918

AF XY:

0.00000995

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000257

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000493

AC:

AN:

1419906

Hom.:

Cov.:

AF XY:

0.00000568

AC XY:

AN XY:

703640

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32290

American (AMR)

AF:

0.00

AC:

AN:

40376

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25464

East Asian (EAS)

AF:

0.00

AC:

AN:

37046

South Asian (SAS)

AF:

0.00

AC:

AN:

81780

European-Finnish (FIN)

AF:

0.00

AC:

AN:

44244

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4922

European-Non Finnish (NFE)

AF:

0.00000639

AC:

AN:

1095018

Other (OTH)

AF:

0.00

AC:

AN:

58766

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000516

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000167

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 18, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: RNASEH2C c.115G>T (p.Asp39Tyr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.1e-05 in 182918 control chromosomes. c.115G>T has been reported in the literature in two compound heterozygous individuals affected with Aicardi Goutieres Syndrome (Ramantani_2010, Garau_2019). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 31130681, 20131292). ClinVar contains an entry for this variant (Variation ID: 464266). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Aicardi-Goutieres syndrome 3

Uncertain:1

Jul 23, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 39 of the RNASEH2C protein (p.Asp39Tyr). This variant is present in population databases (rs773527127, gnomAD 0.003%). This missense change has been observed in individuals with Aicardi‚ÄìGouti√®res syndrome (PMID: 20131292, 31130681). ClinVar contains an entry for this variant (Variation ID: 464266). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Uncertain

0.10

CADD

Benign

(source)

DANN

Benign

0.68

DEOGEN2

Pathogenic

0.86

D;.

Eigen

Benign

-0.44

Eigen_PC

Benign

-0.63

FATHMM_MKL

Benign

0.22

LIST_S2

Benign

0.77

.;T

M_CAP

Pathogenic

0.70

MetaRNN

Pathogenic

0.90

D;D

MetaSVM

Uncertain

0.10

MutationAssessor

Uncertain

2.4

M;.

PhyloP100

0.26

PrimateAI

Uncertain

0.50

PROVEAN

Pathogenic

-5.5

D;D

REVEL

Uncertain

0.53

Sift

Uncertain

0.0070

D;D

Sift4G

Uncertain

0.011

D;D

Polyphen

0.97

D;.

Vest4

0.24

MutPred

0.89

Gain of phosphorylation at D39 (P = 0.0499);Gain of phosphorylation at D39 (P = 0.0499);

MVP

0.84

MPC

1.1

ClinPred

0.95

GERP RS

2.0

PromoterAI

0.026

Neutral

(source)

Varity_R

0.20

gMVP

0.72

Mutation Taster

=33/67

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

rs773527127

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over