19-12806705-C-T

Variant names:

• chr19-12806705-C-T
• rs373265362
• NM_006397.3:c.32C>T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_006397.3(RNASEH2A):​c.32C>T​(p.Thr11Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000955 in 1,570,980 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. T11T) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000056 (0 hom.)
• Consequence: RNASEH2A NM_006397.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 6.97
• Publications: 0 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: Likely_benign. The variant received -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.3131406).

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.32C>T	p.Thr11Ile	missense	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.32C>T	p.Thr11Ile	missense	Exon 1 of 8	ENSP00000221486.4	O75792
	RNASEH2A	ENST00000926045.1		c.32C>T	p.Thr11Ile	missense	Exon 1 of 8	ENSP00000596104.1
	RNASEH2A	ENST00000926044.1		c.32C>T	p.Thr11Ile	missense	Exon 1 of 8	ENSP00000596103.1

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152254 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000112 AC: 2 AN: 179348 AF XY: 0.00

Gnomad AFR exome AF: 0.000190

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000564 AC: 8 AN: 1418726 Hom.: 0 Cov.: 31 AF XY: 0.00000570 AC XY: 4 AN XY: 701816

African (AFR) AF: 0.000123 AC: 4 AN: 32618

American (AMR) AF: 0.00 AC: 0 AN: 37650

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25340

East Asian (EAS) AF: 0.00 AC: 0 AN: 37462

South Asian (SAS) AF: 0.00 AC: 0 AN: 80888

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50220

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5708

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1090112

Other (OTH) AF: 0.0000681 AC: 4 AN: 58728

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152254 Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5 AN XY: 74392

African (AFR) AF: 0.000121 AC: 5 AN: 41460

American (AMR) AF: 0.000131 AC: 2 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68048

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000101 Hom.: 0

Bravo AF: 0.0000869

ESP6500AA AF: 0.000229 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000168 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Aicardi-Goutieres syndrome 4 (1)
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Uncertain	0.040	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T
Eigen	Benign	0.050
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.059	D
MetaRNN	Benign	0.31	T
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		7.0
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.33
Sift	Uncertain	0.026	D
Sift4G	Benign	0.087	T
Polyphen		0.22	B
Vest4		0.38
MVP		0.89
MPC		0.29
ClinPred		0.80	D
GERP RS		4.7
PromoterAI		0.10	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.38
gMVP		0.69
Mutation Taster		=71/29	polymorphism

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: rs373265362; hg19: chr19-12917519;