11-65717747-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_032193.4(RNASEH2C):c.*2036C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.3 in 152,498 control chromosomes in the GnomAD database, including 7,318 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.30 (7291 hom., cov: 33)
  • Exomes 𝑓: 0.35 (27 hom.)
• Consequence: RNASEH2C NM_032193.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.129

Genes affected

RNASEH2C (HGNC:24116): (ribonuclease H2 subunit C) This gene encodes a ribonuclease H subunit that can cleave ribonucleotides from RNA:DNA duplexes. Mutations in this gene cause Aicardi-Goutieres syndrome-3, a disease that causes severe neurologic dysfunction. A pseudogene for this gene has been identified on chromosome Y, near the sex determining region Y (SRY) gene. [provided by RefSeq, Jul 2008]

KAT5 (HGNC:5275): (lysine acetyltransferase 5) The protein encoded by this gene belongs to the MYST family of histone acetyl transferases (HATs) and was originally isolated as an HIV-1 TAT-interactive protein. HATs play important roles in regulating chromatin remodeling, transcription and other nuclear processes by acetylating histone and nonhistone proteins. This protein is a histone acetylase that has a role in DNA repair and apoptosis and is thought to play an important role in signal transduction. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 11-65717747-G-A is Benign according to our data. Variant chr11-65717747-G-A is described in ClinVar as [Benign]. Clinvar id is 305322.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.358 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RNASEH2C	NM_032193.4	c.*2036C>T		3_prime_UTR_variant	4/4	ENST00000308418.10
KAT5	NM_182710.3	c.1264+765G>A		intron_variant		ENST00000341318.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RNASEH2C	ENST00000308418.10	c.*2036C>T		3_prime_UTR_variant	4/4	1	NM_032193.4	P1
KAT5	ENST00000341318.9	c.1264+765G>A		intron_variant		1	NM_182710.3

Frequencies

GnomAD3 genomes AF: 0.300 AC: 45549 AN: 152006 Hom.: 7291 Cov.: 33

Gnomad AFR AF: 0.252

Gnomad AMI AF: 0.413

Gnomad AMR AF: 0.276

Gnomad ASJ AF: 0.328

Gnomad EAS AF: 0.131

Gnomad SAS AF: 0.121

Gnomad FIN AF: 0.262

Gnomad MID AF: 0.332

Gnomad NFE AF: 0.362

Gnomad OTH AF: 0.327

GnomAD4 exome AF: 0.349 AC: 130 AN: 372 Hom.: 27 Cov.: 0 AF XY: 0.362 AC XY: 79 AN XY: 218

Gnomad4 AFR exome AF: 0.167

Gnomad4 AMR exome AF: 0.0714

Gnomad4 ASJ exome AF: 0.500

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.250

Gnomad4 FIN exome AF: 0.333

Gnomad4 NFE exome AF: 0.373

Gnomad4 OTH exome AF: 0.250

GnomAD4 genome AF: 0.300 AC: 45567 AN: 152126 Hom.: 7291 Cov.: 33 AF XY: 0.289 AC XY: 21463 AN XY: 74364

Gnomad4 AFR AF: 0.251

Gnomad4 AMR AF: 0.276

Gnomad4 ASJ AF: 0.328

Gnomad4 EAS AF: 0.131

Gnomad4 SAS AF: 0.122

Gnomad4 FIN AF: 0.262

Gnomad4 NFE AF: 0.362

Gnomad4 OTH AF: 0.323

Alfa AF: 0.347 Hom.: 9941

Bravo AF: 0.302

Asia WGS AF: 0.129 AC: 450 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Aicardi-Goutieres syndrome 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
Cadd	Benign	3.5
Dann	Benign	0.80

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

Publications

LitVar

Other links and lift over

dbSNP: rs3372; hg19: chr11-65485218;