19-12807328-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP3_Moderate

The NM_006397.3(RNASEH2A):c.322C>G(p.Arg108Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000421 in 1,613,988 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. R108W) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000043 (0 hom.)
• Consequence: RNASEH2A NM_006397.3 missense, splice_region
• Scores: Splicing: ADA: 0.4850
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.73

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a strand (size 2) in uniprot entity RNH2A_HUMAN there are 6 pathogenic changes around while only 1 benign (86%) in NM_006397.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-12807328-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 126397.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, not_provided=1, Likely_pathogenic=1}.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.879

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RNASEH2A	NM_006397.3	c.322C>G	p.Arg108Gly	missense_variant, splice_region_variant	3/8	ENST00000221486.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RNASEH2A	ENST00000221486.6	c.322C>G	p.Arg108Gly	missense_variant, splice_region_variant	3/8	1	NM_006397.3	P1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152098 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: 0.00

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

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251478 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135916

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000431 AC: 63 AN: 1461890 Hom.: 0 Cov.: 32 AF XY: 0.0000440 AC XY: 32 AN XY: 727244

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: 0.0000531

Gnomad4 OTH exome AF: 0.0000662

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152098 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74292

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000126 Hom.: 0

Bravo AF: 0.0000416

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 18, 2022

Variant summary: RNASEH2A c.322C>G (p.Arg108Gly) results in a non-conservative amino acid change located in the Ribonuclease HII/HIII domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251478 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.322C>G has been reported in the literature in at least one individual affected with Aicardi Goutieres Syndrome, without strong evidence for causality (Crow_2015). This report does not provide unequivocal conclusions about association of the variant with Aicardi Goutieres Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Aicardi-Goutieres syndrome 4 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 12, 2022

This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 108 of the RNASEH2A protein (p.Arg108Gly). This variant is present in population databases (rs76436818, gnomAD 0.004%). This missense change has been observed in individual(s) with clinical features of Aicardi-Goutieres syndrome (PMID: 25604658). ClinVar contains an entry for this variant (Variation ID: 1372924). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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	Pathogenic	0.60
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.24
Cadd	Pathogenic	28
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.68	D;.
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Pathogenic	0.39	D
MetaRNN	Pathogenic	0.88	D;D
MetaSVM	Uncertain	0.22	D
MutationAssessor	Uncertain	2.9	M;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-6.6	D;.
REVEL	Pathogenic	0.74
Sift	Uncertain	0.0030	D;.
Sift4G	Uncertain	0.0020	D;.
Polyphen		0.85	P;.
Vest4		0.91
MVP		0.97
MPC		0.93
ClinPred		0.91	D
GERP RS		4.0
Varity_R		0.97
gMVP		0.79

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.48
dbscSNV1_RF	Benign	0.38
SpliceAI score (max)		0.050		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

Other links and lift over

dbSNP: rs76436818; hg19: chr19-12918142;