rs76857106

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3PP5

The NM_006397.3(RNASEH2A):​c.109G>A​(p.Gly37Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/23 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G37D) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

RNASEH2A
NM_006397.3 missense

Scores

15
3
1

Clinical Significance

Pathogenic no assertion criteria provided P:1O:1

Conservation

PhyloP100: 8.77
Variant links:
Genes affected
RNASEH2A (HGNC:18518): (ribonuclease H2 subunit A) The protein encoded by this gene is a component of the heterotrimeric type II ribonuclease H enzyme (RNAseH2). RNAseH2 is the major source of ribonuclease H activity in mammalian cells and endonucleolytically cleaves ribonucleotides. It is predicted to remove Okazaki fragment RNA primers during lagging strand DNA synthesis and to excise single ribonucleotides from DNA-DNA duplexes. Mutations in this gene cause Aicardi-Goutieres Syndrome (AGS), a an autosomal recessive neurological disorder characterized by progressive microcephaly and psychomotor retardation, intracranial calcifications, elevated levels of interferon-alpha and white blood cells in the cerebrospinal fluid.[provided by RefSeq, Aug 2009]
THSD8 (HGNC:53785): (thrombospondin type 1 domain containing 8)
HOOK2 (HGNC:19885): (hook microtubule tethering protein 2) Hook proteins are cytosolic coiled-coil proteins that contain conserved N-terminal domains, which attach to microtubules, and more divergent C-terminal domains, which mediate binding to organelles. The Drosophila Hook protein is a component of the endocytic compartment.[supplied by OMIM, Apr 2004]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM1
In a domain RNase H type-2 (size 222) in uniprot entity RNH2A_HUMAN there are 22 pathogenic changes around while only 8 benign (73%) in NM_006397.3
PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
Variant 19-12806782-G-A is Pathogenic according to our data. Variant chr19-12806782-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 4641.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr19-12806782-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
RNASEH2ANM_006397.3 linkuse as main transcriptc.109G>A p.Gly37Ser missense_variant 1/8 ENST00000221486.6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
RNASEH2AENST00000221486.6 linkuse as main transcriptc.109G>A p.Gly37Ser missense_variant 1/81 NM_006397.3 P1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
1425092
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
705196
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
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

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1Other:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Aicardi-Goutieres syndrome 4 Pathogenic:1Other:1
not provided, no classification providedliterature onlyGeneReviews-- -
Pathogenic, no assertion criteria providedliterature onlyOMIMAug 01, 2006- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.94
BayesDel_addAF
Pathogenic
0.59
D
BayesDel_noAF
Pathogenic
0.61
CADD
Pathogenic
36
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.90
D;.
Eigen
Pathogenic
0.94
Eigen_PC
Pathogenic
0.80
FATHMM_MKL
Uncertain
0.92
D
LIST_S2
Pathogenic
1.0
D;D
M_CAP
Pathogenic
0.85
D
MetaRNN
Pathogenic
0.99
D;D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Pathogenic
4.1
H;.
MutationTaster
Benign
1.0
A
PrimateAI
Pathogenic
0.79
T
PROVEAN
Pathogenic
-5.8
D;.
REVEL
Pathogenic
0.98
Sift
Pathogenic
0.0
D;.
Sift4G
Uncertain
0.0080
D;.
Polyphen
1.0
D;.
Vest4
0.96
MutPred
0.97
Gain of phosphorylation at G37 (P = 0.0567);.;
MVP
0.99
MPC
0.81
ClinPred
1.0
D
GERP RS
5.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.8
Varity_R
0.98
gMVP
0.94

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.78
Details are displayed if max score is > 0.2
DS_DG_spliceai
0.78
Position offset: -4

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs76857106; hg19: chr19-12917596; API