19-12806658-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006397.3(RNASEH2A):c.-16T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0418 in 1,572,620 control chromosomes in the GnomAD database, including 1,663 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.031 (102 hom., cov: 32)
  • Exomes 𝑓: 0.043 (1561 hom.)
• Consequence: RNASEH2A NM_006397.3 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.957

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=-0.88).
• BP6: Variant 19-12806658-T-C is Benign according to our data. Variant chr19-12806658-T-C is described in ClinVar as [Benign]. Clinvar id is 328288.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-12806658-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0312 (4745/152242) while in subpopulation NFE AF= 0.048 (3266/67998). AF 95% confidence interval is 0.0467. There are 102 homozygotes in gnomad4. There are 2275 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 102 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RNASEH2A	NM_006397.3	c.-16T>C		5_prime_UTR_variant	1/8	ENST00000221486.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RNASEH2A	ENST00000221486.6	c.-16T>C		5_prime_UTR_variant	1/8	1	NM_006397.3	P1

Frequencies

GnomAD3 genomes AF: 0.0312 AC: 4745 AN: 152122 Hom.: 102 Cov.: 32

Gnomad AFR AF: 0.00835

Gnomad AMI AF: 0.0296

Gnomad AMR AF: 0.0159

Gnomad ASJ AF: 0.0366

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00539

Gnomad FIN AF: 0.0623

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0480

Gnomad OTH AF: 0.0206

GnomAD3 exomes AF: 0.0290 AC: 5346 AN: 184630 Hom.: 130 AF XY: 0.0284 AC XY: 2821 AN XY: 99380

Gnomad AFR exome AF: 0.00718

Gnomad AMR exome AF: 0.0108

Gnomad ASJ exome AF: 0.0365

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00800

Gnomad FIN exome AF: 0.0570

Gnomad NFE exome AF: 0.0437

Gnomad OTH exome AF: 0.0248

GnomAD4 exome AF: 0.0430 AC: 61036 AN: 1420378 Hom.: 1561 Cov.: 31 AF XY: 0.0421 AC XY: 29565 AN XY: 703008

Gnomad4 AFR exome AF: 0.00591

Gnomad4 AMR exome AF: 0.0122

Gnomad4 ASJ exome AF: 0.0364

Gnomad4 EAS exome AF: 0.0000268

Gnomad4 SAS exome AF: 0.00757

Gnomad4 FIN exome AF: 0.0605

Gnomad4 NFE exome AF: 0.0492

Gnomad4 OTH exome AF: 0.0352

GnomAD4 genome AF: 0.0312 AC: 4745 AN: 152242 Hom.: 102 Cov.: 32 AF XY: 0.0306 AC XY: 2275 AN XY: 74438

Gnomad4 AFR AF: 0.00833

Gnomad4 AMR AF: 0.0159

Gnomad4 ASJ AF: 0.0366

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00539

Gnomad4 FIN AF: 0.0623

Gnomad4 NFE AF: 0.0480

Gnomad4 OTH AF: 0.0204

Alfa AF: 0.0394 Hom.: 30

Bravo AF: 0.0272

Asia WGS AF: 0.00433 AC: 15 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 07, 2017

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Aicardi-Goutieres syndrome 4 Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
Cadd	Benign	3.0
Dann	Benign	0.67
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.2

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

Other links and lift over

dbSNP: rs1046220; hg19: chr19-12917472;