rs115373330

Variant names:

• chr2-3546023-C-T
• rs115373330
• NM_002936.6:c.775-152G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_002936.6(RNASEH1):​c.775-152G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0014 in 636,342 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0038 (9 hom., cov: 32)
  • Exomes 𝑓: 0.00065 (2 hom.)
• Consequence: RNASEH1 NM_002936.6 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.373
• Publications: 0 publications found

Genes affected

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 Gene-Disease associations (from GenCC):

• progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 2

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• adult-onset chronic progressive external ophthalmoplegia with mitochondrial myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Leigh syndrome

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ENSG00000286905 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BP6: Variant 2-3546023-C-T is Benign according to our data. Variant chr2-3546023-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1198046.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 9 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002936.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RNASEH1	NM_002936.6	MANE Select	c.775-152G>A		intron	N/A	NP_002927.2
	RNASEH1	NM_001378272.1		c.772-152G>A		intron	N/A	NP_001365201.1
	RNASEH1	NM_001378273.1		c.760-152G>A		intron	N/A	NP_001365202.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RNASEH1	ENST00000315212.4	TSL:1 MANE Select	c.775-152G>A		intron	N/A	ENSP00000313350.3	O60930
	ENSG00000286905	ENST00000658393.1		n.775-152G>A		intron	N/A	ENSP00000499330.1
	RNASEH1	ENST00000861506.1		c.889-152G>A		intron	N/A	ENSP00000531565.1

Frequencies

GnomAD3 genomes AF: 0.00377 AC: 574 AN: 152246 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.0128

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00478

GnomAD4 exome AF: 0.000653 AC: 316 AN: 483978 Hom.: 2 AF XY: 0.000613 AC XY: 158 AN XY: 257950

African (AFR) AF: 0.0132 AC: 179 AN: 13550

American (AMR) AF: 0.00127 AC: 32 AN: 25198

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15588

East Asian (EAS) AF: 0.000287 AC: 9 AN: 31318

South Asian (SAS) AF: 0.000653 AC: 33 AN: 50524

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33350

Middle Eastern (MID) AF: 0.000925 AC: 3 AN: 3242

European-Non Finnish (NFE) AF: 0.0000846 AC: 24 AN: 283766

Other (OTH) AF: 0.00131 AC: 36 AN: 27442

GnomAD4 genome AF: 0.00377 AC: 574 AN: 152364 Hom.: 9 Cov.: 32 AF XY: 0.00356 AC XY: 265 AN XY: 74504

African (AFR) AF: 0.0127 AC: 530 AN: 41578

American (AMR) AF: 0.00118 AC: 18 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5192

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68042

Other (OTH) AF: 0.00473 AC: 10 AN: 2112

Alfa AF: 0.00174 Hom.: 2

Bravo AF: 0.00450

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	2.0
DANN	Benign	0.69
PhyloP100		-0.37
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs115373330; hg19: chr2-3593613;