rs76634951

Variant names:

• chr19-12813343-C-T
• rs76634951
• NM_006397.3:c.777C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_006397.3(RNASEH2A):​c.777C>T​(p.Ser259Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0219 in 1,614,052 control chromosomes in the GnomAD database, including 505 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (38 hom., cov: 32)
  • Exomes 𝑓: 0.022 (467 hom.)
• Consequence: RNASEH2A NM_006397.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.69
• Publications: 5 publications found

Genes affected

RNASEH2A (HGNC:18518): (ribonuclease H2 subunit A) The protein encoded by this gene is a component of the heterotrimeric type II ribonuclease H enzyme (RNAseH2). RNAseH2 is the major source of ribonuclease H activity in mammalian cells and endonucleolytically cleaves ribonucleotides. It is predicted to remove Okazaki fragment RNA primers during lagging strand DNA synthesis and to excise single ribonucleotides from DNA-DNA duplexes. Mutations in this gene cause Aicardi-Goutieres Syndrome (AGS), a an autosomal recessive neurological disorder characterized by progressive microcephaly and psychomotor retardation, intracranial calcifications, elevated levels of interferon-alpha and white blood cells in the cerebrospinal fluid.[provided by RefSeq, Aug 2009]

THSD8 (HGNC:53785): (thrombospondin type 1 domain containing 8)

HOOK2 (HGNC:19885): (hook microtubule tethering protein 2) Hook proteins are cytosolic coiled-coil proteins that contain conserved N-terminal domains, which attach to microtubules, and more divergent C-terminal domains, which mediate binding to organelles. The Drosophila Hook protein is a component of the endocytic compartment.[supplied by OMIM, Apr 2004]

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 19-12813343-C-T is Benign according to our data. Variant chr19-12813343-C-T is described in ClinVar as Benign. ClinVar VariationId is 328297.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.69 with no splicing effect.
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0854 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006397.3. 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
	RNASEH2A	NM_006397.3	MANE Select	c.777C>T	p.Ser259Ser	synonymous	Exon 8 of 8	NP_006388.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RNASEH2A	ENST00000221486.6	TSL:1 MANE Select	c.777C>T	p.Ser259Ser	synonymous	Exon 8 of 8	ENSP00000221486.4	O75792
	RNASEH2A	ENST00000926045.1		c.747C>T	p.Ser249Ser	synonymous	Exon 8 of 8	ENSP00000596104.1
	RNASEH2A	ENST00000926044.1		c.729C>T	p.Ser243Ser	synonymous	Exon 8 of 8	ENSP00000596103.1

Frequencies

GnomAD3 genomes AF: 0.0215 AC: 3275 AN: 152090 Hom.: 38 Cov.: 32

Gnomad AFR AF: 0.0174

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0452

Gnomad ASJ AF: 0.0109

Gnomad EAS AF: 0.0168

Gnomad SAS AF: 0.0215

Gnomad FIN AF: 0.0279

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0192

Gnomad OTH AF: 0.0187

GnomAD2 exomes AF: 0.0293 AC: 7353 AN: 251156 AF XY: 0.0268

Gnomad AFR exome AF: 0.0170

Gnomad AMR exome AF: 0.0918

Gnomad ASJ exome AF: 0.0114

Gnomad EAS exome AF: 0.0175

Gnomad FIN exome AF: 0.0267

Gnomad NFE exome AF: 0.0181

Gnomad OTH exome AF: 0.0225

GnomAD4 exome AF: 0.0219 AC: 32002 AN: 1461844 Hom.: 467 Cov.: 33 AF XY: 0.0216 AC XY: 15741 AN XY: 727222

African (AFR) AF: 0.0180 AC: 603 AN: 33480

American (AMR) AF: 0.0877 AC: 3922 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.0108 AC: 281 AN: 26136

East Asian (EAS) AF: 0.0110 AC: 438 AN: 39696

South Asian (SAS) AF: 0.0239 AC: 2062 AN: 86256

European-Finnish (FIN) AF: 0.0262 AC: 1399 AN: 53418

Middle Eastern (MID) AF: 0.0130 AC: 75 AN: 5768

European-Non Finnish (NFE) AF: 0.0198 AC: 22008 AN: 1111996

Other (OTH) AF: 0.0201 AC: 1214 AN: 60392

GnomAD4 genome AF: 0.0215 AC: 3279 AN: 152208 Hom.: 38 Cov.: 32 AF XY: 0.0224 AC XY: 1668 AN XY: 74404

African (AFR) AF: 0.0174 AC: 721 AN: 41540

American (AMR) AF: 0.0450 AC: 687 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.0109 AC: 38 AN: 3472

East Asian (EAS) AF: 0.0168 AC: 87 AN: 5178

South Asian (SAS) AF: 0.0219 AC: 106 AN: 4830

European-Finnish (FIN) AF: 0.0279 AC: 296 AN: 10616

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0192 AC: 1303 AN: 68006

Other (OTH) AF: 0.0190 AC: 40 AN: 2110

Alfa AF: 0.0185 Hom.: 45

Bravo AF: 0.0236

Asia WGS AF: 0.0170 AC: 60 AN: 3478

EpiCase AF: 0.0170

EpiControl AF: 0.0189

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Aicardi-Goutieres syndrome 4 (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.12
DANN	Benign	0.39
PhyloP100		-1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

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: rs76634951; hg19: chr19-12924157; COSMIC: COSV55551440; COSMIC: COSV55551440;