chr13-50910079-G-A

Variant names:

• chr13-50910079-G-A
• rs886041377
• NM_024570.4:c.3G>A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_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 Likely_pathogenic. Variant got 6 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 1 pathogenic variants. Next in-frame start position is after 90 CDS bases. Genomic position: 50927432. Lost 0.096 part of the original CDS.
• 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 rank	MANE	Protein	UniProt
RNASEH2B	NM_024570.4	c.3G>A	p.Met1?	start_lost	Exon 1 of 11	ENST00000336617.8	NP_078846.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RNASEH2B	ENST00000336617.8	c.3G>A	p.Met1?	start_lost	Exon 1 of 11	1	NM_024570.4	ENSP00000337623.2

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

May 16, 2016

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
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;