rs7247253

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_006397.3(RNASEH2A):​c.550-11T>C variant causes a 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 intron

Scores

2
Splicing: ADA: 0.00009691
2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.352

Publications

4 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]
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]
THSD8 (HGNC:53785): (thrombospondin type 1 domain containing 8)

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 (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.
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 rank MANE Protein UniProt
RNASEH2ANM_006397.3 linkc.550-11T>C intron_variant Intron 5 of 7 ENST00000221486.6 NP_006388.2 O75792

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RNASEH2AENST00000221486.6 linkc.550-11T>C intron_variant Intron 5 of 7 1 NM_006397.3 ENSP00000221486.4 O75792

Frequencies

GnomAD3 genomes
AF:
0.0661
AC:
10048
AN:
152054
Hom.:
532
Cov.:
32
show subpopulations
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
GnomAD2 exomes
AF:
0.0474
AC:
11915
AN:
251484
AF XY:
0.0426
show subpopulations
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 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
show subpopulations
African (AFR)
AF:
0.150
AC:
5025
AN:
33474
American (AMR)
AF:
0.105
AC:
4712
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.0420
AC:
1099
AN:
26136
East Asian (EAS)
AF:
0.0110
AC:
438
AN:
39700
South Asian (SAS)
AF:
0.0283
AC:
2445
AN:
86258
European-Finnish (FIN)
AF:
0.0273
AC:
1459
AN:
53418
Middle Eastern (MID)
AF:
0.0496
AC:
286
AN:
5768
European-Non Finnish (NFE)
AF:
0.0322
AC:
35760
AN:
1111980
Other (OTH)
AF:
0.0420
AC:
2538
AN:
60394
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.473
Heterozygous variant carriers
0
3157
6315
9472
12630
15787
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
1500
3000
4500
6000
7500
<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:
0.0663
AC:
10082
AN:
152172
Hom.:
536
Cov.:
32
AF XY:
0.0655
AC XY:
4876
AN XY:
74404
show subpopulations
African (AFR)
AF:
0.145
AC:
6026
AN:
41502
American (AMR)
AF:
0.0699
AC:
1067
AN:
15274
Ashkenazi Jewish (ASJ)
AF:
0.0427
AC:
148
AN:
3470
East Asian (EAS)
AF:
0.0170
AC:
88
AN:
5170
South Asian (SAS)
AF:
0.0276
AC:
133
AN:
4824
European-Finnish (FIN)
AF:
0.0284
AC:
301
AN:
10614
Middle Eastern (MID)
AF:
0.0680
AC:
20
AN:
294
European-Non Finnish (NFE)
AF:
0.0315
AC:
2140
AN:
67998
Other (OTH)
AF:
0.0553
AC:
117
AN:
2114
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.500
Heterozygous variant carriers
0
466
932
1397
1863
2329
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
112
224
336
448
560
<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:
0.0508
Hom.:
58
Bravo
AF:
0.0742
Asia WGS
AF:
0.0320
AC:
110
AN:
3478

ClinVar

Significance: Benign
Submissions summary: Benign:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:3
-
PreventionGenetics, part of Exact Sciences
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Mar 29, 2016
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

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 -

Nov 12, 2023
Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

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. -

not provided Benign:2
-
Breakthrough Genomics, Breakthrough Genomics
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:not provided

- -

Mar 03, 2015
GeneDx
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Aicardi-Goutieres syndrome 4 Benign:2
Jan 12, 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 04, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.89
CADD
Benign
2.8
DANN
Benign
0.59
PhyloP100
-0.35
Mutation Taster
=100/0
polymorphism (auto)

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

Other links and lift over

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