rs773527127

Variant names:

• chr11-65720644-C-A
• rs773527127
• NM_032193.4:c.115G>T

Your query was ambiguous. Multiple possible variants found:

• chr11-65720644-C-A
• chr11-65720644-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3_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
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.257
• Publications: 3 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
• RNASEH2C-related type 1 interferonopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Aicardi-Goutieres syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.899

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.115G>T	p.Asp39Tyr	missense	Exon 1 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.115G>T	p.Asp39Tyr	missense	Exon 1 of 4	ENSP00000308193.5	Q8TDP1
	RNASEH2C	ENST00000527610.1	TSL:2	c.115G>T	p.Asp39Tyr	missense	Exon 1 of 3	ENSP00000432897.1	E9PN81
	RNASEH2C	ENST00000886953.1		c.115G>T	p.Asp39Tyr	missense	Exon 1 of 4	ENSP00000557012.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000109 AC: 2 AN: 182918 AF XY: 0.00000995

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: 7 AN: 1419906 Hom.: 0 Cov.: 32 AF XY: 0.00000568 AC XY: 4 AN XY: 703640

African (AFR) AF: 0.00 AC: 0 AN: 32290

American (AMR) AF: 0.00 AC: 0 AN: 40376

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25464

East Asian (EAS) AF: 0.00 AC: 0 AN: 37046

South Asian (SAS) AF: 0.00 AC: 0 AN: 81780

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44244

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4922

European-Non Finnish (NFE) AF: 0.00000639 AC: 7 AN: 1095018

Other (OTH) AF: 0.00 AC: 0 AN: 58766

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000516 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000167 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Aicardi-Goutieres syndrome 3 (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.10
CADD	Benign	17
DANN	Benign	0.68
DEOGEN2	Pathogenic	0.86	D
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.77	T
M_CAP	Pathogenic	0.70	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Uncertain	0.10	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		0.26
PrimateAI	Uncertain	0.50	T
PROVEAN	Pathogenic	-5.5	D
REVEL	Uncertain	0.53
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.011	D
Polyphen		0.97	D
Vest4		0.24
MutPred		0.89		Gain of phosphorylation at D39 (P = 0.0499)
MVP		0.84
MPC		1.1
ClinPred		0.95	D
GERP RS		2.0
PromoterAI		0.026	Neutral
Varity_R		0.20
gMVP		0.72
Mutation Taster		=33/67	disease causing

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

Other links and lift over

dbSNP: rs773527127; hg19: chr11-65488115;