rs7247253

chr19-12810306-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006397.3(RNASEH2A):c.550-11T>C variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0396 in 1,614,024 control chromosomes in the GnomAD database, including 1,946 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.066 (536 hom., cov: 32)
  • Exomes 𝑓: 0.037 (1410 hom.)
• Consequence: RNASEH2A NM_006397.3 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00009691
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.352

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 19-12810306-T-C is Benign according to our data. Variant chr19-12810306-T-C is described in ClinVar as [Benign]. Clinvar id is 259973.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-12810306-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.142 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RNASEH2A	NM_006397.3	c.550-11T>C		splice_polypyrimidine_tract_variant, intron_variant		ENST00000221486.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RNASEH2A	ENST00000221486.6	c.550-11T>C		splice_polypyrimidine_tract_variant, intron_variant		1	NM_006397.3	P1

Frequencies

GnomAD3 genomes AF: 0.0661 AC: 10048 AN: 152054 Hom.: 532 Cov.: 32

Gnomad AFR AF: 0.145

Gnomad AMI AF: 0.0461

Gnomad AMR AF: 0.0701

Gnomad ASJ AF: 0.0427

Gnomad EAS AF: 0.0170

Gnomad SAS AF: 0.0271

Gnomad FIN AF: 0.0284

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0315

Gnomad OTH AF: 0.0554

GnomAD3 exomes AF: 0.0474 AC: 11915 AN: 251484 Hom.: 471 AF XY: 0.0426 AC XY: 5795 AN XY: 135916

Gnomad AFR exome AF: 0.142

Gnomad AMR exome AF: 0.109

Gnomad ASJ exome AF: 0.0433

Gnomad EAS exome AF: 0.0176

Gnomad SAS exome AF: 0.0269

Gnomad FIN exome AF: 0.0274

Gnomad NFE exome AF: 0.0301

Gnomad OTH exome AF: 0.0397

GnomAD4 exome AF: 0.0368 AC: 53762 AN: 1461852 Hom.: 1410 Cov.: 33 AF XY: 0.0360 AC XY: 26193 AN XY: 727226

Gnomad4 AFR exome AF: 0.150

Gnomad4 AMR exome AF: 0.105

Gnomad4 ASJ exome AF: 0.0420

Gnomad4 EAS exome AF: 0.0110

Gnomad4 SAS exome AF: 0.0283

Gnomad4 FIN exome AF: 0.0273

Gnomad4 NFE exome AF: 0.0322

Gnomad4 OTH exome AF: 0.0420

GnomAD4 genome AF: 0.0663 AC: 10082 AN: 152172 Hom.: 536 Cov.: 32 AF XY: 0.0655 AC XY: 4876 AN XY: 74404

Gnomad4 AFR AF: 0.145

Gnomad4 AMR AF: 0.0699

Gnomad4 ASJ AF: 0.0427

Gnomad4 EAS AF: 0.0170

Gnomad4 SAS AF: 0.0276

Gnomad4 FIN AF: 0.0284

Gnomad4 NFE AF: 0.0315

Gnomad4 OTH AF: 0.0553

Alfa AF: 0.0476 Hom.: 46

Bravo AF: 0.0742

Asia WGS AF: 0.0320 AC: 110 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Nov 12, 2023	This variant is classified as Benign based on local population frequency. This variant was detected in 20% of patients studied by a panel of primary immunodeficiencies. Number of patients: 19. Only high quality variants are reported. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

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 12, 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

GeneDx

Mar 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
Cadd	Benign	2.8
Dann	Benign	0.59

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000097
dbscSNV1_RF	Benign	0.014
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

Other links and lift over

dbSNP: rs7247253; hg19: chr19-12921120; COSMIC: COSV55551423; COSMIC: COSV55551423;