19-12813191-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_006397.3(RNASEH2A):c.746C>T(p.Ala249Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000545 in 1,613,790 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A249E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000099 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000050 (0 hom.)
• Consequence: RNASEH2A NM_006397.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:6
• Conservation: PhyloP100: 3.20

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

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a domain RNase H type-2 (size 222) in uniprot entity RNH2A_HUMAN there are 22 pathogenic changes around while only 8 benign (73%) in NM_006397.3
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RNASEH2A	NM_006397.3	c.746C>T	p.Ala249Val	missense_variant	7/8	ENST00000221486.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RNASEH2A	ENST00000221486.6	c.746C>T	p.Ala249Val	missense_variant	7/8	1	NM_006397.3	P1

Frequencies

GnomAD3 genomes AF: 0.0000987 AC: 15 AN: 152050 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000656

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000518 AC: 13 AN: 250922 Hom.: 0 AF XY: 0.0000369 AC XY: 5 AN XY: 135642

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000319

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS 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: 0.0000499 AC: 73 AN: 1461740 Hom.: 0 Cov.: 32 AF XY: 0.0000426 AC XY: 31 AN XY: 727138

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000358

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000441

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome AF: 0.0000987 AC: 15 AN: 152050 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74258

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.000656

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000718

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Aicardi-Goutieres syndrome 4 Pathogenic:1 Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 04, 2022	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 249 of the RNASEH2A protein (p.Ala249Val). This variant is present in population databases (rs758719669, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with RNASEH2A-related conditions. ClinVar contains an entry for this variant (Variation ID: 803523). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Apr 14, 2022	ACMG classification criteria: PM2 moderated, BP4 supporting -
Likely pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	3billion	May 22, 2022	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.005%). Missense changes are a common disease-causing mechanism. The variant is in trans with the NM_006397.3:c.717del variant (3billion dataset). The variant is in trans with the other variant. Therefore, this variant is classified as uncertain significanceaccording to the recommendation of ACMG/AMP guideline. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jan 11, 2024

Variant summary: RNASEH2A c.746C>T (p.Ala249Val) results in a non-conservative amino acid change located in the Ribonuclease HII/HIII domain (IPR024567) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.2e-05 in 250922 control chromosomes, predominantly at a frequency of 0.00032 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 1 fold of the estimated maximal expected allele frequency for a pathogenic variant in RNASEH2A causing Aicardi Goutieres Syndrome phenotype (0.00025), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. c.746C>T has been reported in the literature at a homozygous state in two unrelated individuals affected with atypical presentations of Aicardi Goutieres Syndrome (Barcelos_2023). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 37626525). ClinVar contains an entry for this variant (Variation ID: 803523, Likely pathogenic, n=1; VUS, n=5). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 12, 2021

The c.746C>T (p.A249V) alteration is located in exon 7 (coding exon 7) of the RNASEH2A gene. This alteration results from a C to T substitution at nucleotide position 746, causing the alanine (A) at amino acid position 249 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

RNASEH2A-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 10, 2023

The RNASEH2A c.746C>T variant is predicted to result in the amino acid substitution p.Ala249Val. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.031% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-12924005-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.14
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.50	D
Eigen	Benign	0.035
Eigen_PC	Benign	0.011
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.82	T
M_CAP	Uncertain	0.24	D
MetaRNN	Uncertain	0.66	D
MetaSVM	Uncertain	-0.070	T
MutationAssessor	Uncertain	2.8	M
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-3.8	D
REVEL	Uncertain	0.39
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.051	T
Polyphen		0.97	D
Vest4		0.59
MutPred		0.36		Gain of ubiquitination at K247 (P = 0.0671);
MVP		0.90
MPC		0.81
ClinPred		0.89	D
GERP RS		4.6
Varity_R		0.77
gMVP		0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs758719669; hg19: chr19-12924005;