rs62619782

chr19-12810382-T-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006397.3(RNASEH2A):c.615T>A(p.Asp205Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0124 in 1,614,056 control chromosomes in the GnomAD database, including 179 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D205Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.016 (29 hom., cov: 33)
  • Exomes 𝑓: 0.012 (150 hom.)
• Consequence: RNASEH2A NM_006397.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.264

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 Benign. Variant got -18 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
• BP4: Computational evidence support a benign effect (MetaRNN=0.007257074).
• BP6: Variant 19-12810382-T-A is Benign according to our data. Variant chr19-12810382-T-A is described in ClinVar as [Benign]. Clinvar id is 328291.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-12810382-T-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0164 (2493/152260) while in subpopulation AFR AF= 0.0294 (1220/41552). AF 95% confidence interval is 0.028. There are 29 homozygotes in gnomad4. There are 1168 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 29 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RNASEH2A	NM_006397.3	c.615T>A	p.Asp205Glu	missense_variant	6/8	ENST00000221486.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RNASEH2A	ENST00000221486.6	c.615T>A	p.Asp205Glu	missense_variant	6/8	1	NM_006397.3	P1

Frequencies

GnomAD3 genomes AF: 0.0164 AC: 2488 AN: 152142 Hom.: 29 Cov.: 33

Gnomad AFR AF: 0.0293

Gnomad AMI AF: 0.0461

Gnomad AMR AF: 0.0144

Gnomad ASJ AF: 0.0317

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00517

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0120

Gnomad OTH AF: 0.0177

GnomAD3 exomes AF: 0.0109 AC: 2739 AN: 251456 Hom.: 28 AF XY: 0.0105 AC XY: 1429 AN XY: 135906

Gnomad AFR exome AF: 0.0280

Gnomad AMR exome AF: 0.0115

Gnomad ASJ exome AF: 0.0318

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00398

Gnomad FIN exome AF: 0.000739

Gnomad NFE exome AF: 0.0118

Gnomad OTH exome AF: 0.0143

GnomAD4 exome AF: 0.0120 AC: 17491 AN: 1461796 Hom.: 150 Cov.: 33 AF XY: 0.0118 AC XY: 8571 AN XY: 727190

Gnomad4 AFR exome AF: 0.0312

Gnomad4 AMR exome AF: 0.0122

Gnomad4 ASJ exome AF: 0.0313

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00419

Gnomad4 FIN exome AF: 0.00112

Gnomad4 NFE exome AF: 0.0122

Gnomad4 OTH exome AF: 0.0154

GnomAD4 genome AF: 0.0164 AC: 2493 AN: 152260 Hom.: 29 Cov.: 33 AF XY: 0.0157 AC XY: 1168 AN XY: 74456

Gnomad4 AFR AF: 0.0294

Gnomad4 AMR AF: 0.0143

Gnomad4 ASJ AF: 0.0317

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00538

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.0120

Gnomad4 OTH AF: 0.0175

Alfa AF: 0.0138 Hom.: 21

Bravo AF: 0.0178

TwinsUK AF: 0.0132 AC: 49

ALSPAC AF: 0.0122 AC: 47

ESP6500AA AF: 0.0311 AC: 137

ESP6500EA AF: 0.0143 AC: 123

ExAC AF: 0.0109 AC: 1326

Asia WGS AF: 0.00837 AC: 29 AN: 3478

EpiCase AF: 0.0143

EpiControl AF: 0.0149

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Aicardi-Goutieres syndrome 4 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

May 07, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.42
Cadd	Benign	13
Dann	Benign	0.97
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.80	T
MetaRNN	Benign	0.0073	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.69	N
MutationTaster	Benign	0.99	D
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.78	N
REVEL	Benign	0.25
Sift	Benign	0.63	T
Sift4G	Benign	0.79	T
Polyphen		0.0090	B
Vest4		0.038
MutPred		0.50		Loss of stability (P = 0.1427);
MPC		0.20
ClinPred		0.0050	T
GERP RS		-1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.10
gMVP		0.46

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

Publications

LitVar

Other links and lift over

dbSNP: rs62619782; hg19: chr19-12921196; COSMIC: COSV55551843; COSMIC: COSV55551843;