19-12806658-T-C

Variant names:

• chr19-12806658-T-C
• rs1046220
• NM_006397.3:c.-16T>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.-16T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0418 in 1,572,620 control chromosomes in the GnomAD database, including 1,663 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.031 (102 hom., cov: 32)
  • Exomes 𝑓: 0.043 (1561 hom.)
• Consequence: RNASEH2A NM_006397.3 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.957
• Publications: 5 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 (BayesDel_noAF=-0.88).
• BP6: Variant 19-12806658-T-C is Benign according to our data. Variant chr19-12806658-T-C is described in ClinVar as Benign. ClinVar VariationId is 328288.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0312 (4745/152242) while in subpopulation NFE AF = 0.048 (3266/67998). AF 95% confidence interval is 0.0467. There are 102 homozygotes in GnomAd4. There are 2275 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 102 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.-16T>C		5_prime_UTR	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.-16T>C		5_prime_UTR	Exon 1 of 8	ENSP00000221486.4	O75792
	RNASEH2A	ENST00000926045.1		c.-16T>C		5_prime_UTR	Exon 1 of 8	ENSP00000596104.1
	RNASEH2A	ENST00000926044.1		c.-16T>C		5_prime_UTR	Exon 1 of 8	ENSP00000596103.1

Frequencies

GnomAD3 genomes AF: 0.0312 AC: 4745 AN: 152122 Hom.: 102 Cov.: 32

Gnomad AFR AF: 0.00835

Gnomad AMI AF: 0.0296

Gnomad AMR AF: 0.0159

Gnomad ASJ AF: 0.0366

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00539

Gnomad FIN AF: 0.0623

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0480

Gnomad OTH AF: 0.0206

GnomAD2 exomes AF: 0.0290 AC: 5346 AN: 184630 AF XY: 0.0284

Gnomad AFR exome AF: 0.00718

Gnomad AMR exome AF: 0.0108

Gnomad ASJ exome AF: 0.0365

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0570

Gnomad NFE exome AF: 0.0437

Gnomad OTH exome AF: 0.0248

GnomAD4 exome AF: 0.0430 AC: 61036 AN: 1420378 Hom.: 1561 Cov.: 31 AF XY: 0.0421 AC XY: 29565 AN XY: 703008

African (AFR) AF: 0.00591 AC: 192 AN: 32508

American (AMR) AF: 0.0122 AC: 466 AN: 38258

Ashkenazi Jewish (ASJ) AF: 0.0364 AC: 923 AN: 25376

East Asian (EAS) AF: 0.0000268 AC: 1 AN: 37370

South Asian (SAS) AF: 0.00757 AC: 614 AN: 81148

European-Finnish (FIN) AF: 0.0605 AC: 3040 AN: 50262

Middle Eastern (MID) AF: 0.00385 AC: 22 AN: 5710

European-Non Finnish (NFE) AF: 0.0492 AC: 53706 AN: 1090960

Other (OTH) AF: 0.0352 AC: 2072 AN: 58786

GnomAD4 genome AF: 0.0312 AC: 4745 AN: 152242 Hom.: 102 Cov.: 32 AF XY: 0.0306 AC XY: 2275 AN XY: 74438

African (AFR) AF: 0.00833 AC: 346 AN: 41536

American (AMR) AF: 0.0159 AC: 243 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0366 AC: 127 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5170

South Asian (SAS) AF: 0.00539 AC: 26 AN: 4822

European-Finnish (FIN) AF: 0.0623 AC: 662 AN: 10622

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0480 AC: 3266 AN: 67998

Other (OTH) AF: 0.0204 AC: 43 AN: 2112

Alfa AF: 0.0394 Hom.: 30

Bravo AF: 0.0272

Asia WGS AF: 0.00433 AC: 15 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	3.0
DANN	Benign	0.67
PhyloP100		-0.96
PromoterAI		0.029	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.2
Mutation Taster		=300/0	polymorphism (auto)

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: rs1046220; hg19: chr19-12917472;