2-3549068-G-A

Position:

• chr2-3549068-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 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).

• 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

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]

ENSG00000286905 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 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 id is 372199.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-3549068-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RNASEH1	NM_002936.6	c.554C>T	p.Ala185Val	missense_variant	5/8	ENST00000315212.4	NP_002927.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RNASEH1	ENST00000315212.4	c.554C>T	p.Ala185Val	missense_variant	5/8	1	NM_002936.6	ENSP00000313350.3
ENSG00000286905	ENST00000658393.1	n.554C>T		non_coding_transcript_exon_variant	5/12			ENSP00000499330.1

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 2 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 29, 2015

- -

Computational scores

Source: dbNSFP v4.3

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
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs1057517675; hg19: chr2-3596658;