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GeneBe

19-12806705-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_006397.3(RNASEH2A):c.32C>T(p.Thr11Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000955 in 1,570,980 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 (★). Synonymous variant affecting the same amino acid position (i.e. T11T) has been classified as Benign.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000056 ( 0 hom. )

Consequence

RNASEH2A
NM_006397.3 missense

Scores

9
10

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.97
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 Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.3131406).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
RNASEH2ANM_006397.3 linkuse as main transcriptc.32C>T p.Thr11Ile missense_variant 1/8 ENST00000221486.6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
RNASEH2AENST00000221486.6 linkuse as main transcriptc.32C>T p.Thr11Ile missense_variant 1/81 NM_006397.3 P1

Frequencies

GnomAD3 genomes
AF:
0.0000460
AC:
7
AN:
152254
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000121
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000112
AC:
2
AN:
179348
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
95874
show subpopulations
Gnomad AFR exome
AF:
0.000190
Gnomad AMR exome
AF:
0.00
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:
0.00000564
AC:
8
AN:
1418726
Hom.:
0
Cov.:
31
AF XY:
0.00000570
AC XY:
4
AN XY:
701816
show subpopulations
Gnomad4 AFR exome
AF:
0.000123
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:
0.0000681
GnomAD4 genome
AF:
0.0000460
AC:
7
AN:
152254
Hom.:
0
Cov.:
32
AF XY:
0.0000672
AC XY:
5
AN XY:
74392
show subpopulations
Gnomad4 AFR
AF:
0.000121
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000554
Hom.:
0
Bravo
AF:
0.0000869
ESP6500AA
AF:
0.000229
AC:
1
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000168
AC:
2

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Aicardi-Goutieres syndrome 4 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInvitaeMar 19, 2022This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 11 of the RNASEH2A protein (p.Thr11Ile). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with RNASEH2A-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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
0.23
BayesDel_addAF
Uncertain
0.040
T
BayesDel_noAF
Benign
-0.18
Cadd
Benign
23
Dann
Uncertain
1.0
DEOGEN2
Benign
0.30
T;.
Eigen
Benign
0.050
Eigen_PC
Benign
0.15
FATHMM_MKL
Uncertain
0.90
D
LIST_S2
Uncertain
0.88
D;D
M_CAP
Benign
0.059
D
MetaRNN
Benign
0.31
T;T
MetaSVM
Uncertain
-0.21
T
MutationAssessor
Uncertain
2.2
M;.
MutationTaster
Benign
1.0
D
PrimateAI
Uncertain
0.70
T
PROVEAN
Benign
-1.8
N;.
REVEL
Uncertain
0.33
Sift
Uncertain
0.026
D;.
Sift4G
Benign
0.087
T;.
Polyphen
0.22
B;.
Vest4
0.38
MVP
0.89
MPC
0.29
ClinPred
0.80
D
GERP RS
4.7
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.2
Varity_R
0.38
gMVP
0.69

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

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

Other links and lift over

dbSNP: rs373265362; hg19: chr19-12917519; API