rs62619782

Variant names:

• chr19-12810382-T-A
• rs62619782
• NM_006397.3:c.615T>A

Your query was ambiguous. Multiple possible variants found:

• chr19-12810382-T-A
• chr19-12810382-T-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006397.3(RNASEH2A):​c.615T>A​(p.Asp205Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0124 in 1,614,056 control chromosomes in the GnomAD database, including 179 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D205Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.016 (29 hom., cov: 33)
  • Exomes 𝑓: 0.012 (150 hom.)
• Consequence: RNASEH2A NM_006397.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.264
• Publications: 9 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007257074).
• BP6: Variant 19-12810382-T-A is Benign according to our data. Variant chr19-12810382-T-A is described in ClinVar as Benign. ClinVar VariationId is 328291.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0164 (2493/152260) while in subpopulation AFR AF = 0.0294 (1220/41552). AF 95% confidence interval is 0.028. There are 29 homozygotes in GnomAd4. There are 1168 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 29 AR,AD gene

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.615T>A	p.Asp205Glu	missense	Exon 6 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.615T>A	p.Asp205Glu	missense	Exon 6 of 8	ENSP00000221486.4	O75792
	RNASEH2A	ENST00000926045.1		c.585T>A	p.Asp195Glu	missense	Exon 6 of 8	ENSP00000596104.1
	RNASEH2A	ENST00000926044.1		c.567T>A	p.Asp189Glu	missense	Exon 6 of 8	ENSP00000596103.1

Frequencies

GnomAD3 genomes AF: 0.0164 AC: 2488 AN: 152142 Hom.: 29 Cov.: 33

Gnomad AFR AF: 0.0293

Gnomad AMI AF: 0.0461

Gnomad AMR AF: 0.0144

Gnomad ASJ AF: 0.0317

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00517

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0120

Gnomad OTH AF: 0.0177

GnomAD2 exomes AF: 0.0109 AC: 2739 AN: 251456 AF XY: 0.0105

Gnomad AFR exome AF: 0.0280

Gnomad AMR exome AF: 0.0115

Gnomad ASJ exome AF: 0.0318

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.000739

Gnomad NFE exome AF: 0.0118

Gnomad OTH exome AF: 0.0143

GnomAD4 exome AF: 0.0120 AC: 17491 AN: 1461796 Hom.: 150 Cov.: 33 AF XY: 0.0118 AC XY: 8571 AN XY: 727190

African (AFR) AF: 0.0312 AC: 1044 AN: 33474

American (AMR) AF: 0.0122 AC: 546 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0313 AC: 818 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00419 AC: 361 AN: 86258

European-Finnish (FIN) AF: 0.00112 AC: 60 AN: 53420

Middle Eastern (MID) AF: 0.0319 AC: 184 AN: 5768

European-Non Finnish (NFE) AF: 0.0122 AC: 13547 AN: 1111924

Other (OTH) AF: 0.0154 AC: 930 AN: 60394

GnomAD4 genome AF: 0.0164 AC: 2493 AN: 152260 Hom.: 29 Cov.: 33 AF XY: 0.0157 AC XY: 1168 AN XY: 74456

African (AFR) AF: 0.0294 AC: 1220 AN: 41552

American (AMR) AF: 0.0143 AC: 219 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0317 AC: 110 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5174

South Asian (SAS) AF: 0.00538 AC: 26 AN: 4830

European-Finnish (FIN) AF: 0.000471 AC: 5 AN: 10624

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.0120 AC: 817 AN: 68012

Other (OTH) AF: 0.0175 AC: 37 AN: 2112

Alfa AF: 0.0138 Hom.: 21

Bravo AF: 0.0178

TwinsUK AF: 0.0132 AC: 49

ALSPAC AF: 0.0122 AC: 47

ESP6500AA AF: 0.0311 AC: 137

ESP6500EA AF: 0.0143 AC: 123

ExAC AF: 0.0109 AC: 1326

Asia WGS AF: 0.00837 AC: 29 AN: 3478

EpiCase AF: 0.0143

EpiControl AF: 0.0149

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	13
DANN	Benign	0.97
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.80	T
MetaRNN	Benign	0.0073	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.69	N
PhyloP100		-0.26
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.78	N
REVEL	Benign	0.25
Sift	Benign	0.63	T
Sift4G	Benign	0.79	T
Polyphen		0.0090	B
Vest4		0.038
MutPred		0.50		Loss of stability (P = 0.1427)
MPC		0.20
ClinPred		0.0050	T
GERP RS		-1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.10
gMVP		0.46
Mutation Taster		=88/12	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs62619782; hg19: chr19-12921196; COSMIC: COSV55551843; COSMIC: COSV55551843;