rs143534021

chr19-12813107-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM1 BP4_Strong BP6_Very_Strong BS1

The NM_006397.3(RNASEH2A):c.662A>G(p.Lys221Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000626 in 1,614,168 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00048 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00064 (2 hom.)
• Consequence: RNASEH2A NM_006397.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.345

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 -14 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=0.010812551).
• BP6: Variant 19-12813107-A-G is Benign according to our data. Variant chr19-12813107-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 328294.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-12813107-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000642 (938/1461872) while in subpopulation MID AF= 0.00433 (25/5768). AF 95% confidence interval is 0.00301. There are 2 homozygotes in gnomad4_exome. There are 529 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RNASEH2A	NM_006397.3	c.662A>G	p.Lys221Arg	missense_variant	7/8	ENST00000221486.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RNASEH2A	ENST00000221486.6	c.662A>G	p.Lys221Arg	missense_variant	7/8	1	NM_006397.3	P1

Frequencies

GnomAD3 genomes AF: 0.000473 AC: 72 AN: 152184 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000500

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000641 AC: 161 AN: 251354 Hom.: 1 AF XY: 0.000736 AC XY: 100 AN XY: 135862

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00261

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000581

Gnomad OTH exome AF: 0.000978

GnomAD4 exome AF: 0.000642 AC: 938 AN: 1461872 Hom.: 2 Cov.: 32 AF XY: 0.000727 AC XY: 529 AN XY: 727232

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.000291

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00252

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000558

Gnomad4 OTH exome AF: 0.000894

GnomAD4 genome AF: 0.000479 AC: 73 AN: 152296 Hom.: 0 Cov.: 32 AF XY: 0.000537 AC XY: 40 AN XY: 74464

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000500

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000621 Hom.: 0

Bravo AF: 0.000552

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000725 AC: 88

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000818

EpiControl AF: 0.000652

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Aicardi-Goutieres syndrome 4 Benign:4

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Dec 07, 2014	- -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	RNASEH2A: BP4 -

RNASEH2A-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 14, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.48
Cadd	Benign	14
Dann	Benign	0.36
DEOGEN2	Benign	0.23	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	-0.34	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-0.38	N
REVEL	Benign	0.25
Sift	Benign	0.70	T
Sift4G	Benign	0.57	T
Polyphen		0.0010	B
Vest4		0.12
MVP		0.62
MPC		0.17
ClinPred		0.0072	T
GERP RS		-4.8
Varity_R		0.084
gMVP		0.42

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs143534021; hg19: chr19-12923921; COSMIC: COSV99677477;