rs62619782

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

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. 16/21 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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.264

Publications

9 publications found

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 was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

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 VariationId is 328291.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 29 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RNASEH2A	NM_006397.3 link	c.615T>A	p.Asp205Glu	missense_variant	Exon 6 of 8	ENST00000221486.6	NP_006388.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RNASEH2A	ENST00000221486.6 link	c.615T>A	p.Asp205Glu	missense_variant	Exon 6 of 8	1	NM_006397.3	ENSP00000221486.4

Frequencies

GnomAD3 genomes

AF:

0.0164

AC:

2488

AN:

152142

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.0109

AC:

2739

AN:

251456

AF XY:

0.0105

show subpopulations

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 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.:

AF XY:

0.0118

AC XY:

8571

AN XY:

727190

show subpopulations

African (AFR)

AF:

0.0312

AC:

1044

AN:

33474

American (AMR)

AF:

0.0122

AC:

546

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0313

AC:

818

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.00419

AC:

361

AN:

86258

European-Finnish (FIN)

AF:

0.00112

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.0319

AC:

184

AN:

5768

European-Non Finnish (NFE)

AF:

0.0122

AC:

13547

AN:

1111924

Other (OTH)

AF:

0.0154

AC:

930

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

942

1884

2826

3768

4710

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

544

1088

1632

2176

2720

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0164

AC:

2493

AN:

152260

Hom.:

Cov.:

AF XY:

0.0157

AC XY:

1168

AN XY:

74456

show subpopulations

African (AFR)

AF:

0.0294

AC:

1220

AN:

41552

American (AMR)

AF:

0.0143

AC:

219

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.0317

AC:

110

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5174

South Asian (SAS)

AF:

0.00538

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.000471

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.0544

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0120

AC:

817

AN:

68012

Other (OTH)

AF:

0.0175

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

125

250

375

500

625

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

150

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0138

Hom.:

Bravo

AF:

0.0178

TwinsUK

AF:

0.0132

AC:

ALSPAC

AF:

0.0122

AC:

ESP6500AA

AF:

0.0311

AC:

137

ESP6500EA

AF:

0.0143

AC:

123

ExAC

AF:

0.0109

AC:

1326

Asia WGS

AF:

0.00837

AC:

AN:

3478

EpiCase

AF:

0.0143

EpiControl

AF:

0.0149

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Aicardi-Goutieres syndrome 4

Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Jan 03, 2024

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.42

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.21

Eigen

Benign

-0.73

Eigen_PC

Benign

-0.63

FATHMM_MKL

Benign

0.65

LIST_S2

Benign

0.80

MetaRNN

Benign

0.0073

MetaSVM

Benign

-0.91

MutationAssessor

Benign

0.69

PhyloP100

-0.26

PrimateAI

Benign

0.43

PROVEAN

Benign

-0.78

REVEL

Benign

0.25

Sift

Benign

0.63

Sift4G

Benign

0.79

Polyphen

0.0090

Vest4

0.038

MutPred

0.50

Loss of stability (P = 0.1427);

MPC

0.20

ClinPred

0.0050

GERP RS

-1.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.10

gMVP

0.46

Mutation Taster

=88/12

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over