rs773830258

Positions:

• chr11-65720703-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1 PM2 BP4_Strong

The NM_032193.4(RNASEH2C):​c.56C>G​(p.Ala19Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000009 in 1,443,826 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000090 (0 hom.)
• Consequence: RNASEH2C NM_032193.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -1.45

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM1: In a chain Ribonuclease H2 subunit C (size 163) in uniprot entity RNH2C_HUMAN there are 16 pathogenic changes around while only 2 benign (89%) in NM_032193.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.01659444).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RNASEH2C	NM_032193.4	c.56C>G	p.Ala19Gly	missense_variant	1/4	ENST00000308418.10	NP_115569.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RNASEH2C	ENST00000308418.10	c.56C>G	p.Ala19Gly	missense_variant	1/4	1	NM_032193.4	ENSP00000308193.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000601 AC: 13 AN: 216140 Hom.: 0 AF XY: 0.0000420 AC XY: 5 AN XY: 119132

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000395

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000900 AC: 13 AN: 1443826 Hom.: 0 Cov.: 32 AF XY: 0.00000836 AC XY: 6 AN XY: 717712

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000297

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000718

ExAC AF: 0.0000498 AC: 6

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Aicardi-Goutieres syndrome 3 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Jun 28, 2018	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 16, 2022	This sequence change replaces alanine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 19 of the RNASEH2C protein (p.Ala19Gly). This variant is present in population databases (rs773830258, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with RNASEH2C-related conditions. ClinVar contains an entry for this variant (Variation ID: 582219). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glycine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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	0.086
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	0.048
DANN	Benign	0.75
DEOGEN2	Benign	0.016	T;.
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.042	N
LIST_S2	Benign	0.49	.;T
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.017	T;T
MetaSVM	Benign	-0.49	T
MutationAssessor	Benign	0.55	N;.
PrimateAI	Benign	0.41	T
PROVEAN	Benign	0.12	N;N
REVEL	Benign	0.21
Sift	Benign	0.97	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;.
Vest4		0.088
MutPred		0.29		Gain of glycosylation at S18 (P = 0.0852);Gain of glycosylation at S18 (P = 0.0852);
MVP		0.12
MPC		0.40
ClinPred		0.057	T
GERP RS		-8.7
Varity_R		0.099
gMVP		0.47

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

Other links and lift over

dbSNP: rs773830258; hg19: chr11-65488174;