chr19-12806728-C-A

Variant names:

• chr19-12806728-C-A
• rs1039519462
• NM_006397.3:c.55C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006397.3(RNASEH2A):​c.55C>A​(p.Pro19Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000706 in 1,416,770 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P19A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: RNASEH2A NM_006397.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.421
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09316069).

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.55C>A	p.Pro19Thr	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.55C>A	p.Pro19Thr	missense	Exon 1 of 8	ENSP00000221486.4	O75792
	RNASEH2A	ENST00000926045.1		c.55C>A	p.Pro19Thr	missense	Exon 1 of 8	ENSP00000596104.1
	RNASEH2A	ENST00000926044.1		c.55C>A	p.Pro19Thr	missense	Exon 1 of 8	ENSP00000596103.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.06e-7 AC: 1 AN: 1416770 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 700476

African (AFR) AF: 0.00 AC: 0 AN: 32682

American (AMR) AF: 0.00 AC: 0 AN: 37108

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25294

East Asian (EAS) AF: 0.00 AC: 0 AN: 37554

South Asian (SAS) AF: 0.00 AC: 0 AN: 80766

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50184

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5652

European-Non Finnish (NFE) AF: 9.18e-7 AC: 1 AN: 1088834

Other (OTH) AF: 0.00 AC: 0 AN: 58696

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.056	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	16
DANN	Benign	0.95
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.17	N
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.051	D
MetaRNN	Benign	0.093	T
MetaSVM	Benign	-0.51	T
MutationAssessor	Benign	1.8	L
PhyloP100		0.42
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.14
Sift	Benign	0.33	T
Sift4G	Benign	0.47	T
Polyphen		0.089	B
Vest4		0.38
MutPred		0.36		Loss of disorder (P = 0.039)
MVP		0.78
MPC		0.25
ClinPred		0.18	T
GERP RS		1.4
PromoterAI		-0.085	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.25
gMVP		0.59
Mutation Taster		=86/14	polymorphism

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: rs1039519462; hg19: chr19-12917542;