rs75184679

Variant names:

• chr13-50945445-G-A
• rs75184679
• NM_024570.4:c.529G>A

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 12P and 2B. PS3 PP5_Very_Strong BP4 BS2_Supporting

The NM_024570.4(RNASEH2B):​c.529G>A​(p.Ala177Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00202 in 1,612,756 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000384595: Structural and functional studies, including in patient fibroblasts and mouse embryonic fibroblasts from an orthologous knock-in model, have demonstrated that the p.Ala177Thr substitution reduces RNase H2 subunit expression, disrupts the interaction interface of RNASEH2B with RNASEH2C, impairs complex stability, and reduces cellular RNase H2 activity (PMID:26903602" and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. A177A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (5 hom.)
• Consequence: RNASEH2B NM_024570.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:59
• Conservation: PhyloP100: 4.69
• Publications: 72 publications found

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 Gene-Disease associations (from GenCC):

• Aicardi-Goutieres syndrome 2

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• RNASEH2B-related type 1 interferonopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Aicardi-Goutieres syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• prostate cancer

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000384595: Structural and functional studies, including in patient fibroblasts and mouse embryonic fibroblasts from an orthologous knock-in model, have demonstrated that the p.Ala177Thr substitution reduces RNase H2 subunit expression, disrupts the interaction interface of RNASEH2B with RNASEH2C, impairs complex stability, and reduces cellular RNase H2 activity (PMID: 26903602; PMID: 21177858; PMID: 21177854).; SCV000652369: Experimental studies have shown that this missense change affects RNASEH2B function (PMID: 19015152, 19034401, 26903602).; SCV000803481: "PS3-Moderate => PS3 downgraded in strength to Moderate (PMID:25274781)."; SCV001427209: "Well-established in vivo and in vitro functional studies of the p.Ala177Thr variant strongly suggest a deleterious effect to the protein that is sufficient to be disease-causing (Mackenzie et al., 2016; Pizzi et al., 2014)."; SCV002061178: "Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID:25274781; 19015152, 26903602) - PS3_moderate."; SCV002061858: PS3; SCV002495930: Functional studies, including a knock-in mouse model predict that this variant will impact the protein and result in downstream instability (Lim 2015 PMID:26182405, Pizzi 2015 PMID:25274781, Mackenzie 2016 PMID:26903602).; SCV004171884: Experimental studies have shown that this missense change affects RNASEH2B function (Mackenzie et al., 2016).; SCV005045054: "functional studies have shown a modest alteration of enzymatic activity and homozygous knock-in mice recapitulate the interferon-stimulated gene signature observed in human patients with AGS (Chon H et al., PMID: 19015152; Mackenzie KJ et al., PMID: 26903602; Perrino FW et al., PMID: 19034401; Pizzi S et al., PMID: 25274781)."; SCV005088784: Functional studies have shown that this variant affects RNASEH2B function [PMID: 19015152, 19034401, 26903602].; SCV000329498: Lymphoblastoid cells derived from a patient who harbored the A177T variant showed a destabilizing effect on the RNase H2 protein; however, it is unclear if this perturbation is solely due to the effect of the A177T variant. PMID: 25274781; SCV001247787: PS3:Supporting; SCV006325527: Functional studies have shown that this missense change affects RNASEH2B function (PMID: 19015152, 19034401, 26903602).; SCV000540198: In vitro functional studies provide conflicting data ( Lim 2015 and Pizzi 2015).; SCV004106595: Functional studies have shown that this variant destabilizes the RNase H2 protein complex (Pizzi et al. 2015. PubMed ID: 25274781).
• PP5: Variant 13-50945445-G-A is Pathogenic according to our data. Variant chr13-50945445-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 1262.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.051852375). . Strength limited to SUPPORTING due to the PP5.
• BS2: High Homozygotes in GnomAdExome4 at 5 AD,AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024570.4. 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
	RNASEH2B	NM_024570.4	MANE Select	c.529G>A	p.Ala177Thr	missense	Exon 7 of 11	NP_078846.2	Q5TBB1-1
	RNASEH2B	NM_001411023.1		c.529G>A	p.Ala177Thr	missense	Exon 7 of 11	NP_001397952.1	A0A2R8Y883
	RNASEH2B	NM_001142279.2		c.529G>A	p.Ala177Thr	missense	Exon 7 of 10	NP_001135751.1	Q5TBB1-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RNASEH2B	ENST00000336617.8	TSL:1 MANE Select	c.529G>A	p.Ala177Thr	missense	Exon 7 of 11	ENSP00000337623.2	Q5TBB1-1
	RNASEH2B	ENST00000646960.1		c.529G>A	p.Ala177Thr	missense	Exon 7 of 13	ENSP00000496481.1	A0A2R8Y7R8
	RNASEH2B	ENST00000643159.1		c.439G>A	p.Ala147Thr	missense	Exon 9 of 16	ENSP00000495587.1	A0A2R8YEH2

Frequencies

GnomAD3 genomes AF: 0.00145 AC: 221 AN: 152170 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000831

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00229

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00140 AC: 351 AN: 251300 AF XY: 0.00158

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000896

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.00228

Gnomad OTH exome AF: 0.000816

GnomAD4 exome AF: 0.00208 AC: 3031 AN: 1460468 Hom.: 5 Cov.: 30 AF XY: 0.00206 AC XY: 1499 AN XY: 726628

African (AFR) AF: 0.000389 AC: 13 AN: 33458

American (AMR) AF: 0.000917 AC: 41 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.000153 AC: 4 AN: 26112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.00154 AC: 133 AN: 86210

European-Finnish (FIN) AF: 0.0000749 AC: 4 AN: 53390

Middle Eastern (MID) AF: 0.00208 AC: 12 AN: 5756

European-Non Finnish (NFE) AF: 0.00245 AC: 2718 AN: 1110802

Other (OTH) AF: 0.00176 AC: 106 AN: 60348

GnomAD4 genome AF: 0.00145 AC: 221 AN: 152288 Hom.: 0 Cov.: 32 AF XY: 0.00141 AC XY: 105 AN XY: 74470

African (AFR) AF: 0.000289 AC: 12 AN: 41562

American (AMR) AF: 0.00261 AC: 40 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000831 AC: 4 AN: 4812

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00229 AC: 156 AN: 68016

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.00178 Hom.: 1

Bravo AF: 0.00150

TwinsUK AF: 0.00324 AC: 12

ALSPAC AF: 0.00337 AC: 13

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00291 AC: 25

ExAC AF: 0.00130 AC: 158

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00289

EpiControl AF: 0.00302

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
34	-	-	Aicardi-Goutieres syndrome 2 (34)
17	-	-	not provided (17)
2	-	-	Aicardi Goutieres syndrome (2)
1	-	-	Abnormality of the nervous system (1)
1	-	-	Autism spectrum disorder (1)
1	-	-	Cerebral palsy (1)
1	-	-	Hereditary spastic paraplegia (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	RNASEH2B-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	0.0044	T
BayesDel_noAF	Pathogenic	0.23
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.49	T
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.86	D
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.052	T
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		4.7
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.61
Sift	Benign	0.22	T
Sift4G	Benign	0.20	T
Polyphen		0.99	D
Vest4		0.79
MVP		0.89
MPC		0.059
ClinPred		0.076	T
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.35
gMVP		0.38
Mutation Taster		=23/77	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs75184679; hg19: chr13-51519581; COSMIC: COSV107407431; COSMIC: COSV107407431;