NM_006397.3:c.33A>G

Variant names:

• chr19-12806706-A-G
• rs11554400
• NM_006397.3:c.33A>G

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.33A>G​(p.Thr11Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0394 in 1,570,774 control chromosomes in the GnomAD database, including 1,884 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.066 (543 hom., cov: 32)
  • Exomes 𝑓: 0.036 (1341 hom.)
• Consequence: RNASEH2A NM_006397.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.66
• Publications: 4 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=-0.89).
• BP6: Variant 19-12806706-A-G is Benign according to our data. Variant chr19-12806706-A-G is described in ClinVar as Benign. ClinVar VariationId is 259971.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.65 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.143 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.33A>G	p.Thr11Thr	synonymous	Exon 1 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.33A>G	p.Thr11Thr	synonymous	Exon 1 of 8	ENSP00000221486.4	O75792
	RNASEH2A	ENST00000926045.1		c.33A>G	p.Thr11Thr	synonymous	Exon 1 of 8	ENSP00000596104.1
	RNASEH2A	ENST00000926044.1		c.33A>G	p.Thr11Thr	synonymous	Exon 1 of 8	ENSP00000596103.1

Frequencies

GnomAD3 genomes AF: 0.0663 AC: 10088 AN: 152178 Hom.: 538 Cov.: 32

Gnomad AFR AF: 0.145

Gnomad AMI AF: 0.0462

Gnomad AMR AF: 0.0703

Gnomad ASJ AF: 0.0427

Gnomad EAS AF: 0.0169

Gnomad SAS AF: 0.0271

Gnomad FIN AF: 0.0283

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0315

Gnomad OTH AF: 0.0554

GnomAD2 exomes AF: 0.0467 AC: 8373 AN: 179230 AF XY: 0.0423

Gnomad AFR exome AF: 0.139

Gnomad AMR exome AF: 0.104

Gnomad ASJ exome AF: 0.0439

Gnomad EAS exome AF: 0.0168

Gnomad FIN exome AF: 0.0275

Gnomad NFE exome AF: 0.0302

Gnomad OTH exome AF: 0.0398

GnomAD4 exome AF: 0.0364 AC: 51690 AN: 1418478 Hom.: 1341 Cov.: 31 AF XY: 0.0358 AC XY: 25117 AN XY: 701666

African (AFR) AF: 0.150 AC: 4902 AN: 32588

American (AMR) AF: 0.101 AC: 3773 AN: 37536

Ashkenazi Jewish (ASJ) AF: 0.0419 AC: 1061 AN: 25322

East Asian (EAS) AF: 0.0105 AC: 394 AN: 37494

South Asian (SAS) AF: 0.0284 AC: 2300 AN: 80876

European-Finnish (FIN) AF: 0.0275 AC: 1383 AN: 50226

Middle Eastern (MID) AF: 0.0497 AC: 284 AN: 5710

European-Non Finnish (NFE) AF: 0.0322 AC: 35105 AN: 1090006

Other (OTH) AF: 0.0424 AC: 2488 AN: 58720

GnomAD4 genome AF: 0.0665 AC: 10124 AN: 152296 Hom.: 543 Cov.: 32 AF XY: 0.0657 AC XY: 4895 AN XY: 74476

African (AFR) AF: 0.146 AC: 6059 AN: 41546

American (AMR) AF: 0.0701 AC: 1073 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0427 AC: 148 AN: 3470

East Asian (EAS) AF: 0.0170 AC: 88 AN: 5180

South Asian (SAS) AF: 0.0275 AC: 133 AN: 4834

European-Finnish (FIN) AF: 0.0283 AC: 301 AN: 10622

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.0315 AC: 2143 AN: 68020

Other (OTH) AF: 0.0553 AC: 117 AN: 2116

Alfa AF: 0.0467 Hom.: 133

Bravo AF: 0.0745

Asia WGS AF: 0.0320 AC: 112 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	6.5
DANN	Benign	0.67
PhyloP100		-1.7
PromoterAI		-0.083	Neutral
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs11554400; hg19: chr19-12917520;