dbSNP rs4072375: ENSG00000286905:n.*85-2780T>C (chr2-3539691-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The ENST00000658393.1(ENSG00000286905):n.*85-2780T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.404 in 152,024 control chromosomes in the GnomAD database, including 13,729 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.40 ( 13729 hom., cov: 31)

Consequence

ENSG00000286905
ENST00000658393.1 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.881

Publications

6 publications found

Variant links:

Genes affected

ENSG00000286905 (HGNC:):

ENSG00000286905 links:

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

RNASEH1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.97).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.588 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RNASEH1	NR_148532.2 link	n.1019-2780T>C		intron_variant	Intron 8 of 10
RNASEH1	NR_148534.2 link	n.1019-2780T>C		intron_variant	Intron 8 of 11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENSG00000286905	ENST00000658393.1 link	n.*85-2780T>C		intron_variant	Intron 8 of 11			ENSP00000499330.1
ENSG00000286905	ENST00000654051.1 link	n.*85-2780T>C		intron_variant	Intron 8 of 10			ENSP00000499604.1

Frequencies

GnomAD3 genomes

AF:

0.404

AC:

61365

AN:

151906

Hom.:

13701

Cov.:

show subpopulations

Gnomad AFR

AF:

0.594

Gnomad AMI

AF:

0.548

Gnomad AMR

AF:

0.276

Gnomad ASJ

AF:

0.364

Gnomad EAS

AF:

0.260

Gnomad SAS

AF:

0.294

Gnomad FIN

AF:

0.216

Gnomad MID

AF:

0.462

Gnomad NFE

AF:

0.365

Gnomad OTH

AF:

0.406

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.404

AC:

61432

AN:

152024

Hom.:

13729

Cov.:

AF XY:

0.392

AC XY:

29135

AN XY:

74324

show subpopulations

African (AFR)

AF:

0.594

AC:

24624

AN:

41452

American (AMR)

AF:

0.275

AC:

4200

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.364

AC:

1263

AN:

3470

East Asian (EAS)

AF:

0.260

AC:

1343

AN:

5160

South Asian (SAS)

AF:

0.293

AC:

1411

AN:

4818

European-Finnish (FIN)

AF:

0.216

AC:

2288

AN:

10570

Middle Eastern (MID)

AF:

0.463

AC:

136

AN:

294

European-Non Finnish (NFE)

AF:

0.365

AC:

24819

AN:

67966

Other (OTH)

AF:

0.402

AC:

849

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1769

3537

5306

7074

8843

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

566

1132

1698

2264

2830

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.351

Hom.:

4901

Bravo

AF:

0.418

Asia WGS

AF:

0.281

AC:

982

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.97

CADD

Benign

0.40

(source)

DANN

Benign

0.17

PhyloP100

-0.88

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over