rs939276490

Variant names:

• chr11-65720330-T-C
• rs939276490
• NM_032193.4:c.260A>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_032193.4(RNASEH2C):​c.260A>G​(p.Glu87Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,882 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. E87K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: RNASEH2C NM_032193.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.42
• Publications: 0 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.40637127).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032193.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RNASEH2C	NM_032193.4	MANE Select	c.260A>G	p.Glu87Gly	missense	Exon 2 of 4	NP_115569.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RNASEH2C	ENST00000308418.10	TSL:1 MANE Select	c.260A>G	p.Glu87Gly	missense	Exon 2 of 4	ENSP00000308193.5
	RNASEH2C	ENST00000527610.1	TSL:2	c.260A>G	p.Glu87Gly	missense	Exon 2 of 3	ENSP00000432897.1
	RNASEH2C	ENST00000886953.1		c.260A>G	p.Glu87Gly	missense	Exon 2 of 4	ENSP00000557012.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461882 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727242

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1112012

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Aicardi-Goutieres syndrome 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.058	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.44	T
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.71	T
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.41	T
MetaSVM	Uncertain	-0.083	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		3.4
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.42
Sift	Uncertain	0.029	D
Sift4G	Benign	0.14	T
Polyphen		0.75	P
Vest4		0.36
MutPred		0.55		Loss of sheet (P = 0.0181)
MVP		0.61
MPC		1.2
ClinPred		0.92	D
GERP RS		3.9
PromoterAI		-0.0096	Neutral
Varity_R		0.37
gMVP		0.55
Mutation Taster		=84/16	polymorphism

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

Other links and lift over

dbSNP: rs939276490; hg19: chr11-65487801;