rs1057517675

Variant names:

• chr2-3549068-G-A
• rs1057517675
• NM_002936.6:c.554C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_002936.6(RNASEH1):​c.554C>T​(p.Ala185Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,460,752 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. A185A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: RNASEH1 NM_002936.6 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.48
• Publications: 7 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: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.971
• PP5: Variant 2-3549068-G-A is Pathogenic according to our data. Variant chr2-3549068-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 372199.Status of the report is no_assertion_criteria_provided, 0 stars.

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.554C>T	p.Ala185Val	missense	Exon 5 of 8	NP_002927.2
	RNASEH1	NM_001378272.1		c.551C>T	p.Ala184Val	missense	Exon 5 of 8	NP_001365201.1
	RNASEH1	NM_001378273.1		c.539C>T	p.Ala180Val	missense	Exon 5 of 8	NP_001365202.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RNASEH1	ENST00000315212.4	TSL:1 MANE Select	c.554C>T	p.Ala185Val	missense	Exon 5 of 8	ENSP00000313350.3	O60930
	ENSG00000286905	ENST00000658393.1		n.554C>T		non_coding_transcript_exon	Exon 5 of 12	ENSP00000499330.1
	RNASEH1	ENST00000861506.1		c.668C>T	p.Ala223Val	missense	Exon 6 of 9	ENSP00000531565.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1460752 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 726764

African (AFR) AF: 0.00 AC: 0 AN: 33444

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39674

South Asian (SAS) AF: 0.00 AC: 0 AN: 86220

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111046

Other (OTH) AF: 0.00 AC: 0 AN: 60354

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.85	D
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.33	D
MutationAssessor	Pathogenic	3.9	H
PhyloP100		7.5
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-3.7	D
REVEL	Uncertain	0.59
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.85		Loss of disorder (P = 0.0549)
MVP		0.91
MPC		0.93
ClinPred		1.0	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.79
gMVP		0.94
Mutation Taster		=37/63	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs1057517675; hg19: chr2-3596658;