11-65718256-T-G

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.*1527A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.885 in 231,548 control chromosomes in the GnomAD database, including 91,111 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.88 (59041 hom., cov: 32)
  • Exomes 𝑓: 0.90 (32070 hom.)
• Consequence: RNASEH2C NM_032193.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.452

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=-0.84).
• BP6: Variant 11-65718256-T-G is Benign according to our data. Variant chr11-65718256-T-G is described in ClinVar as [Benign]. Clinvar id is 305334.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.91 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RNASEH2C	NM_032193.4	c.*1527A>C		3_prime_UTR_variant	4/4	ENST00000308418.10
KAT5	NM_182710.3	c.1265-334T>G		intron_variant		ENST00000341318.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RNASEH2C	ENST00000308418.10	c.*1527A>C		3_prime_UTR_variant	4/4	1	NM_032193.4	P1
KAT5	ENST00000341318.9	c.1265-334T>G		intron_variant		1	NM_182710.3

Frequencies

GnomAD3 genomes AF: 0.879 AC: 133747 AN: 152074 Hom.: 58993 Cov.: 32

Gnomad AFR AF: 0.830

Gnomad AMI AF: 0.846

Gnomad AMR AF: 0.879

Gnomad ASJ AF: 0.895

Gnomad EAS AF: 0.894

Gnomad SAS AF: 0.719

Gnomad FIN AF: 0.902

Gnomad MID AF: 0.877

Gnomad NFE AF: 0.916

Gnomad OTH AF: 0.880

GnomAD4 exome AF: 0.896 AC: 71105 AN: 79356 Hom.: 32070 Cov.: 2 AF XY: 0.890 AC XY: 36685 AN XY: 41196

Gnomad4 AFR exome AF: 0.823

Gnomad4 AMR exome AF: 0.878

Gnomad4 ASJ exome AF: 0.887

Gnomad4 EAS exome AF: 0.901

Gnomad4 SAS exome AF: 0.740

Gnomad4 FIN exome AF: 0.913

Gnomad4 NFE exome AF: 0.922

Gnomad4 OTH exome AF: 0.903

GnomAD4 genome AF: 0.880 AC: 133856 AN: 152192 Hom.: 59041 Cov.: 32 AF XY: 0.877 AC XY: 65257 AN XY: 74398

Gnomad4 AFR AF: 0.830

Gnomad4 AMR AF: 0.880

Gnomad4 ASJ AF: 0.895

Gnomad4 EAS AF: 0.894

Gnomad4 SAS AF: 0.720

Gnomad4 FIN AF: 0.902

Gnomad4 NFE AF: 0.916

Gnomad4 OTH AF: 0.878

Alfa AF: 0.909 Hom.: 105243

Bravo AF: 0.878

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 13, 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	-0.84
Cadd	Benign	1.2
Dann	Benign	0.65

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

Publications

LitVar

Other links and lift over

dbSNP: rs521678; hg19: chr11-65485727;