13-50910079-G-A

Position:

• chr13-50910079-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1 PS1_Moderate PM2 PP5_Moderate

The NM_024570.4(RNASEH2B):​c.3G>A​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000763 in 1,311,152 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 (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.6e-7 (0 hom.)
• Consequence: RNASEH2B NM_024570.4 start_lost
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.31

Genes affected

RNASEH2B (HGNC:25671): (ribonuclease H2 subunit B) RNase H2 is composed of a single catalytic subunit (A) and two non-catalytic subunits (B and C) and specifically degrades the RNA of RNA:DNA hybrids. The protein encoded by this gene is the non-catalytic B subunit of RNase H2, which is thought to play a role in DNA replication. Multiple transcript variants encoding different isoforms have been found for this gene. Defects in this gene are a cause of Aicardi-Goutieres syndrome type 2 (AGS2). [provided by RefSeq, Nov 2008]

RNASEH2B-AS1 (HGNC:39967): (RNASEH2B antisense RNA 1)

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in NM_024570.4 (RNASEH2B) was described as [Conflicting_classifications_of_pathogenicity] in ClinVar as 661979
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 13-50910079-G-A is Pathogenic according to our data. Variant chr13-50910079-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 280090.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RNASEH2B	NM_024570.4	c.3G>A	p.Met1?	start_lost	1/11	ENST00000336617.8
RNASEH2B-AS1	NR_046552.1	n.230+404C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RNASEH2B	ENST00000336617.8	c.3G>A	p.Met1?	start_lost	1/11	1	NM_024570.4	P3
RNASEH2B-AS1	ENST00000596992.5	n.112+404C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.63e-7 AC: 1 AN: 1311152 Hom.: 0 Cov.: 31 AF XY: 0.00000155 AC XY: 1 AN XY: 645094

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000450

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

May 16, 2016

The c.3 G>A pathogenic variant in the RNASEH2B gene has been reported previously in the presence of another RNASEH2B pathogenic variant, in two related individuals with Aicardi-Goutieres syndrome (Rice et al., 2013). Data from control individuals was not sufficient to assess whether c.3 G>A may be a common benign variant in the general population. As this pathogenic variant changes the translation initiator Methionine codon, the resultant protein is described as p.Met1?, using a question mark to signify that it is not known if the loss of Met1 means that all protein translation is completely prevented or if an abnormal protein is produced using an alternate Methionine. Therefore, we interpret c.3 G>A as a pathogenic variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.46
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0059	T;.;.;.;.;.;.;.;.;.;.;.
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.35	N
LIST_S2	Uncertain	0.90	D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.51	D
MutationTaster	Benign	1.0	D;D
PROVEAN	Benign	-0.89	N;N;.;.;.;.;.;.;.;.;.;.
REVEL	Uncertain	0.64
Sift	Pathogenic	0.0	D;D;.;.;.;.;.;.;.;.;.;.
Sift4G	Pathogenic	0.0	D;D;.;.;.;.;.;.;.;.;.;.
Polyphen		0.049	B;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.70
MutPred		0.97		Gain of catalytic residue at D6 (P = 0);Gain of catalytic residue at D6 (P = 0);Gain of catalytic residue at D6 (P = 0);Gain of catalytic residue at D6 (P = 0);Gain of catalytic residue at D6 (P = 0);Gain of catalytic residue at D6 (P = 0);Gain of catalytic residue at D6 (P = 0);Gain of catalytic residue at D6 (P = 0);Gain of catalytic residue at D6 (P = 0);Gain of catalytic residue at D6 (P = 0);Gain of catalytic residue at D6 (P = 0);Gain of catalytic residue at D6 (P = 0);
MVP		0.84
ClinPred		1.0	D
GERP RS		2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.97
gMVP		0.40

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: rs886041377; hg19: chr13-51484215;