11-65717686-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_032193.4(RNASEH2C):c.*2097C>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 0.0307 in 152,830 control chromosomes in the GnomAD database, including 98 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.031 (98 hom., cov: 32)
  • Exomes 𝑓: 0.027 (0 hom.)
• Consequence: RNASEH2C NM_032193.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.337

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=-0.87).
• BP6: Variant 11-65717686-G-A is Benign according to our data. Variant chr11-65717686-G-A is described in ClinVar as [Benign]. Clinvar id is 305321.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0307 (4677/152274) while in subpopulation NFE AF= 0.0466 (3170/68026). AF 95% confidence interval is 0.0452. There are 98 homozygotes in gnomad4. There are 2225 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 98 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RNASEH2C	NM_032193.4	c.*2097C>T		3_prime_UTR_variant	4/4	ENST00000308418.10
KAT5	NM_182710.3	c.1264+704G>A		intron_variant		ENST00000341318.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RNASEH2C	ENST00000308418.10	c.*2097C>T		3_prime_UTR_variant	4/4	1	NM_032193.4	P1
KAT5	ENST00000341318.9	c.1264+704G>A		intron_variant		1	NM_182710.3

Frequencies

GnomAD3 genomes AF: 0.0307 AC: 4678 AN: 152156 Hom.: 98 Cov.: 32

Gnomad AFR AF: 0.00960

Gnomad AMI AF: 0.00330

Gnomad AMR AF: 0.0263

Gnomad ASJ AF: 0.0510

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00600

Gnomad FIN AF: 0.0404

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0466

Gnomad OTH AF: 0.0292

GnomAD4 exome AF: 0.0270 AC: 15 AN: 556 Hom.: 0 Cov.: 0 AF XY: 0.0290 AC XY: 9 AN XY: 310

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0297

Gnomad4 OTH exome AF: 0.0417

GnomAD4 genome AF: 0.0307 AC: 4677 AN: 152274 Hom.: 98 Cov.: 32 AF XY: 0.0299 AC XY: 2225 AN XY: 74446

Gnomad4 AFR AF: 0.00958

Gnomad4 AMR AF: 0.0262

Gnomad4 ASJ AF: 0.0510

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00601

Gnomad4 FIN AF: 0.0404

Gnomad4 NFE AF: 0.0466

Gnomad4 OTH AF: 0.0294

Alfa AF: 0.0411 Hom.: 51

Bravo AF: 0.0306

Asia WGS AF: 0.00433 AC: 16 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 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	-0.87
Cadd	Benign	3.6
Dann	Benign	0.55

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: rs4645934; hg19: chr11-65485157;