2-3548003-T-C

Position:

• chr2-3548003-T-C

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_002936.6(RNASEH1):​c.702A>G​(p.Ala234=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00866 in 1,613,838 control chromosomes in the GnomAD database, including 88 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0065 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0089 (86 hom.)
• Consequence: RNASEH1 NM_002936.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.54

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]

ACMG classification

Verdict is Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 2-3548003-T-C is Benign according to our data. Variant chr2-3548003-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 673568.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.54 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RNASEH1	NM_002936.6	c.702A>G	p.Ala234=	synonymous_variant	7/8	ENST00000315212.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RNASEH1	ENST00000315212.4	c.702A>G	p.Ala234=	synonymous_variant	7/8	1	NM_002936.6	P1
RNASEH1	ENST00000436842.5	c.*808A>G		3_prime_UTR_variant, NMD_transcript_variant	7/8	2

Frequencies

GnomAD3 genomes AF: 0.00650 AC: 990 AN: 152206 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00176

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0109

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0109

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00673 AC: 1692 AN: 251480 Hom.: 14 AF XY: 0.00650 AC XY: 883 AN XY: 135914

Gnomad AFR exome AF: 0.00141

Gnomad AMR exome AF: 0.00147

Gnomad ASJ exome AF: 0.00198

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.0123

Gnomad NFE exome AF: 0.0114

Gnomad OTH exome AF: 0.00603

GnomAD4 exome AF: 0.00889 AC: 12986 AN: 1461514 Hom.: 86 Cov.: 31 AF XY: 0.00856 AC XY: 6226 AN XY: 727092

Gnomad4 AFR exome AF: 0.00140

Gnomad4 AMR exome AF: 0.00161

Gnomad4 ASJ exome AF: 0.00230

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0131

Gnomad4 NFE exome AF: 0.0105

Gnomad4 OTH exome AF: 0.00782

GnomAD4 genome AF: 0.00649 AC: 989 AN: 152324 Hom.: 2 Cov.: 32 AF XY: 0.00596 AC XY: 444 AN XY: 74476

Gnomad4 AFR AF: 0.00176

Gnomad4 AMR AF: 0.00261

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0109

Gnomad4 NFE AF: 0.0109

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00849 Hom.: 6

Bravo AF: 0.00554

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00889

EpiControl AF: 0.00865

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2024	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 28, 2021	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	RNASEH1: BP4, BP7, BS1, BS2 -

RNASEH1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 04, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.13
DANN	Benign	0.64

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

Other links and lift over

dbSNP: rs143510329; hg19: chr2-3595593;