11-65720644-C-T

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_032193.4(RNASEH2C):​c.115G>A​(p.Asp39Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000572 in 1,572,138 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict 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. D39Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: RNASEH2C NM_032193.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.10439736).

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>A	p.Asp39Asn	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>A	p.Asp39Asn	missense	Exon 1 of 4	ENSP00000308193.5	Q8TDP1
	RNASEH2C	ENST00000527610.1	TSL:2	c.115G>A	p.Asp39Asn	missense	Exon 1 of 3	ENSP00000432897.1	E9PN81
	RNASEH2C	ENST00000886953.1		c.115G>A	p.Asp39Asn	missense	Exon 1 of 4	ENSP00000557012.1

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152232 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000547 AC: 1 AN: 182918 AF XY: 0.00

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: 0.0000128

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000211 AC: 3 AN: 1419906 Hom.: 0 Cov.: 32 AF XY: 0.00000284 AC XY: 2 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: 0.00000274 AC: 3 AN: 1095018

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

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152232 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74376

African (AFR) AF: 0.00 AC: 0 AN: 41474

American (AMR) AF: 0.00 AC: 0 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000189 Hom.: 0

ExAC AF: 0.00000836 AC: 1

ClinVar

ClinVar submissions

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	0.081
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	6.7
DANN	Benign	0.86
DEOGEN2	Uncertain	0.48	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.022	N
LIST_S2	Benign	0.71	T
M_CAP	Uncertain	0.27	D
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	-0.42	N
PhyloP100		0.26
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.69	N
REVEL	Benign	0.21
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.093
MutPred		0.67		Loss of helix (P = 0.1299)
MVP		0.16
MPC		0.39
ClinPred		0.033	T
GERP RS		2.0
PromoterAI		0.083	Neutral
Varity_R		0.29
gMVP		0.44
Mutation Taster		=79/21	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: rs773527127; hg19: chr11-65488115;