rs112380097

Variant names:

• chr2-3558529-A-G
• rs112380097
• ENST00000438436.5:n.119A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000797888.1(RNASEH1-DT):​n.108+8A>G variant causes a splice region, intron 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. 1/1 splice prediction tools predict no significant impact on normal splicing. 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 ENST00000797888.1 splice_region, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.13
• Publications: 0 publications found

Genes affected

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

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 -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000797888.1. 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-DT	NR_038429.1		n.144A>G		non_coding_transcript_exon	Exon 1 of 3
	RNASEH1-DT	NR_038430.1		n.143A>G		non_coding_transcript_exon	Exon 1 of 3
	RNASEH1-DT	NR_038431.1		n.143A>G		non_coding_transcript_exon	Exon 1 of 2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RNASEH1-DT	ENST00000438436.5	TSL:1	n.119A>G		non_coding_transcript_exon	Exon 1 of 3
	RNASEH1-DT	ENST00000426725.4	TSL:2	n.155A>G		non_coding_transcript_exon	Exon 1 of 2
	RNASEH1-DT	ENST00000664922.4		n.155A>G		non_coding_transcript_exon	Exon 1 of 3

Frequencies

GnomAD3 genomes AF: 0.0385 AC: 5861 AN: 152216 Hom.: 178 Cov.: 34

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.: 4 AF XY: 0.0264 AC XY: 3527 AN XY: 133778

African (AFR) AF: 0.0753 AC: 396 AN: 5258

American (AMR) AF: 0.0196 AC: 114 AN: 5802

Ashkenazi Jewish (ASJ) AF: 0.0273 AC: 228 AN: 8364

East Asian (EAS) AF: 0.00170 AC: 24 AN: 14144

South Asian (SAS) AF: 0.0539 AC: 1520 AN: 28212

European-Finnish (FIN) AF: 0.00914 AC: 161 AN: 17620

Middle Eastern (MID) AF: 0.0474 AC: 57 AN: 1202

European-Non Finnish (NFE) AF: 0.0205 AC: 3269 AN: 159190

Other (OTH) AF: 0.0256 AC: 395 AN: 15456

GnomAD4 genome AF: 0.0385 AC: 5866 AN: 152332 Hom.: 177 Cov.: 34 AF XY: 0.0383 AC XY: 2851 AN XY: 74494

African (AFR) AF: 0.0804 AC: 3344 AN: 41576

American (AMR) AF: 0.0202 AC: 309 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0325 AC: 113 AN: 3472

East Asian (EAS) AF: 0.0125 AC: 65 AN: 5182

South Asian (SAS) AF: 0.0573 AC: 277 AN: 4830

European-Finnish (FIN) AF: 0.00772 AC: 82 AN: 10624

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.0222 AC: 1511 AN: 68016

Other (OTH) AF: 0.0279 AC: 59 AN: 2116

Alfa AF: 0.0319 Hom.: 16

Bravo AF: 0.0405

Asia WGS AF: 0.0450 AC: 156 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	3.1
DANN	Benign	0.59
PhyloP100		-1.1
PromoterAI		0.069	Neutral
Mutation Taster		=300/0	polymorphism (auto)

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: rs112380097; hg19: chr2-3606119;