chr13-50930752-A-G

Variant names:

• chr13-50930752-A-G
• rs201078944
• NM_024570.4:c.314A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_024570.4(RNASEH2B):​c.314A>G​(p.Asp105Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,678 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/24 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D105A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RNASEH2B NM_024570.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.443
• Publications: 0 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), PanelApp Australia, Ambry Genetics, G2P
• Aicardi-Goutieres syndrome

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

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RNASEH2B	NM_024570.4	c.314A>G	p.Asp105Gly	missense_variant	Exon 4 of 11	ENST00000336617.8	NP_078846.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RNASEH2B	ENST00000336617.8	c.314A>G	p.Asp105Gly	missense_variant	Exon 4 of 11	1	NM_024570.4	ENSP00000337623.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460678 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 726770

African (AFR) AF: 0.00 AC: 0 AN: 33448

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110914

Other (OTH) AF: 0.00 AC: 0 AN: 60360

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.068	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	14
DANN	Benign	0.89
DEOGEN2	Benign	0.35	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;T;.;.
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.82	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;.;.;T;T;T
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.17	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Benign	0.17	N;N;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
PhyloP100		0.44
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.7	N;N;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Benign	0.26
Sift	Benign	0.69	T;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Benign	0.52	T;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Polyphen		0.0	B;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.16
MutPred		0.57		Gain of catalytic residue at A104 (P = 0.0072);Gain of catalytic residue at A104 (P = 0.0072);Gain of catalytic residue at A104 (P = 0.0072);Gain of catalytic residue at A104 (P = 0.0072);.;Gain of catalytic residue at A104 (P = 0.0072);.;Gain of catalytic residue at A104 (P = 0.0072);Gain of catalytic residue at A104 (P = 0.0072);Gain of catalytic residue at A104 (P = 0.0072);Gain of catalytic residue at A104 (P = 0.0072);Gain of catalytic residue at A104 (P = 0.0072);.;.;.;.;.;.;.;.;
MVP		0.81
MPC		0.060
ClinPred		0.23	T
GERP RS		0.81
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.29
gMVP		0.42
Mutation Taster		=70/30	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.31		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.31		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs201078944; hg19: chr13-51504888;