Genetic Variant RNASEH1-DT:n.62A>G (chr2-3558529-A-G) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000438436.4(RNASEH1-DT):n.62A>G variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0295 in 407,580 control chromosomes in the GnomAD database, including 297 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.039 ( 177 hom., cov: 34)

Exomes 𝑓: 0.024 ( 120 hom. )

Consequence

RNASEH1-DT
ENST00000438436.4 non_coding_transcript_exon

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -1.13

Variant links:

Genes affected

RNASEH1-DT (HGNC:49289): (RNASEH1 divergent transcript)

RNASEH1-DT links:

RNASEH1 (HGNC:18466): (ribonuclease H1) This gene encodes an endonuclease that specifically degrades the RNA of RNA-DNA hybrids and plays a key role in DNA replication and repair. Alternate in-frame start codon initiation results in the production of alternate isoforms that are directed to the mitochondria or to the nucleus. The production of the mitochondrial isoform is modulated by an upstream open reading frame (uORF). Mutations in this gene have been found in individuals with progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 2. Alternative splicing results in additional coding and non-coding transcript variants. Pseudogenes of this gene have been defined on chromosomes 2 and 17. [provided by RefSeq, Jul 2017]

RNASEH1 links:

ENSG00000286905 (HGNC:):

ENSG00000286905 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BP6

Variant 2-3558529-A-G is Benign according to our data. Variant chr2-3558529-A-G is described in ClinVar as [Benign]. Clinvar id is 1246180.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0782 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RNASEH1	NM_002936.6 link	c.-269T>C		upstream_gene_variant		ENST00000315212.4	NP_002927.2	O60930E5KN15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RNASEH1	ENST00000315212.4 link	c.-269T>C		upstream_gene_variant		1	NM_002936.6	ENSP00000313350.3		O60930
ENSG00000286905	ENST00000658393.1 link	n.-269T>C		upstream_gene_variant				ENSP00000499330.1

Frequencies

GnomAD3 genomes

AF:

0.0385

AC:

5861

AN:

152216

Hom.:

178

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0804

Gnomad AMI

AF:

0.0998

Gnomad AMR

AF:

0.0202

Gnomad ASJ

AF:

0.0325

Gnomad EAS

AF:

0.0123

Gnomad SAS

AF:

0.0581

Gnomad FIN

AF:

0.00772

Gnomad MID

AF:

0.0570

Gnomad NFE

AF:

0.0222

Gnomad OTH

AF:

0.0282

GnomAD4 exome

AF:

0.0241

AC:

6164

AN:

255248

Hom.:

120

Cov.:

AF XY:

0.0264

AC XY:

3527

AN XY:

133778

show subpopulations

Gnomad4 AFR exome

AF:

0.0753

Gnomad4 AMR exome

AF:

0.0196

Gnomad4 ASJ exome

AF:

0.0273

Gnomad4 EAS exome

AF:

0.00170

Gnomad4 SAS exome

AF:

0.0539

Gnomad4 FIN exome

AF:

0.00914

Gnomad4 NFE exome

AF:

0.0205

Gnomad4 OTH exome

AF:

0.0256

GnomAD4 genome

AF:

0.0385

AC:

5866

AN:

152332

Hom.:

177

Cov.:

AF XY:

0.0383

AC XY:

2851

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.0804

Gnomad4 AMR

AF:

0.0202

Gnomad4 ASJ

AF:

0.0325

Gnomad4 EAS

AF:

0.0125

Gnomad4 SAS

AF:

0.0573

Gnomad4 FIN

AF:

0.00772

Gnomad4 NFE

AF:

0.0222

Gnomad4 OTH

AF:

0.0279

Alfa

AF:

0.0319

Hom.:

Bravo

AF:

0.0405

Asia WGS

AF:

0.0450

AC:

156

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 25, 2018

GeneDx

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

-0.80

CADD

Benign

3.1

DANN

Benign

0.59

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