rs7247253

Variant names:

• chr19-12810306-T-C
• rs7247253
• NM_006397.3:c.550-11T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006397.3(RNASEH2A):​c.550-11T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0396 in 1,614,024 control chromosomes in the GnomAD database, including 1,946 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.066 (536 hom., cov: 32)
  • Exomes 𝑓: 0.037 (1410 hom.)
• Consequence: RNASEH2A NM_006397.3 intron
• Scores: Splicing: ADA: 0.00009691
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.352
• 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]

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]

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 19-12810306-T-C is Benign according to our data. Variant chr19-12810306-T-C is described in ClinVar as Benign. ClinVar VariationId is 259973.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.142 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RNASEH2A	NM_006397.3	MANE Select	c.550-11T>C		intron	N/A	NP_006388.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RNASEH2A	ENST00000221486.6	TSL:1 MANE Select	c.550-11T>C		intron	N/A	ENSP00000221486.4
	HOOK2	ENST00000589765.1	TSL:5	n.41+14872A>G		intron	N/A
	RNASEH2A	ENST00000593017.2	TSL:2	n.836-11T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0661 AC: 10048 AN: 152054 Hom.: 532 Cov.: 32

Gnomad AFR AF: 0.145

Gnomad AMI AF: 0.0461

Gnomad AMR AF: 0.0701

Gnomad ASJ AF: 0.0427

Gnomad EAS AF: 0.0170

Gnomad SAS AF: 0.0271

Gnomad FIN AF: 0.0284

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0315

Gnomad OTH AF: 0.0554

GnomAD2 exomes AF: 0.0474 AC: 11915 AN: 251484 AF XY: 0.0426

Gnomad AFR exome AF: 0.142

Gnomad AMR exome AF: 0.109

Gnomad ASJ exome AF: 0.0433

Gnomad EAS exome AF: 0.0176

Gnomad FIN exome AF: 0.0274

Gnomad NFE exome AF: 0.0301

Gnomad OTH exome AF: 0.0397

GnomAD4 exome AF: 0.0368 AC: 53762 AN: 1461852 Hom.: 1410 Cov.: 33 AF XY: 0.0360 AC XY: 26193 AN XY: 727226

African (AFR) AF: 0.150 AC: 5025 AN: 33474

American (AMR) AF: 0.105 AC: 4712 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0420 AC: 1099 AN: 26136

East Asian (EAS) AF: 0.0110 AC: 438 AN: 39700

South Asian (SAS) AF: 0.0283 AC: 2445 AN: 86258

European-Finnish (FIN) AF: 0.0273 AC: 1459 AN: 53418

Middle Eastern (MID) AF: 0.0496 AC: 286 AN: 5768

European-Non Finnish (NFE) AF: 0.0322 AC: 35760 AN: 1111980

Other (OTH) AF: 0.0420 AC: 2538 AN: 60394

GnomAD4 genome AF: 0.0663 AC: 10082 AN: 152172 Hom.: 536 Cov.: 32 AF XY: 0.0655 AC XY: 4876 AN XY: 74404

African (AFR) AF: 0.145 AC: 6026 AN: 41502

American (AMR) AF: 0.0699 AC: 1067 AN: 15274

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

East Asian (EAS) AF: 0.0170 AC: 88 AN: 5170

South Asian (SAS) AF: 0.0276 AC: 133 AN: 4824

European-Finnish (FIN) AF: 0.0284 AC: 301 AN: 10614

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

European-Non Finnish (NFE) AF: 0.0315 AC: 2140 AN: 67998

Other (OTH) AF: 0.0553 AC: 117 AN: 2114

Alfa AF: 0.0508 Hom.: 58

Bravo AF: 0.0742

Asia WGS AF: 0.0320 AC: 110 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	2.8
DANN	Benign	0.59
PhyloP100		-0.35
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000097
dbscSNV1_RF	Benign	0.014
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: rs7247253; hg19: chr19-12921120; COSMIC: COSV55551423; COSMIC: COSV55551423;