chr19-12806658-T-C

Position:

chr19-12806658-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.957

Variant links:

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]

RNASEH2A links:

THSD8 (HGNC:53785): (thrombospondin type 1 domain containing 8)

THSD8 links:

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]

HOOK2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 GnomAd4 at 102 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RNASEH2A	NM_006397.3 linkuse as main transcript	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 linkuse as main transcript	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.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.0421

AC XY:

29565

AN XY:

703008

show subpopulations

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.:

AF XY:

0.0306

AC XY:

2275

AN XY:

74438

show subpopulations

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.:

Bravo

AF:

0.0272

Asia WGS

AF:

0.00433

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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. -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over