rs535111

Variant names:

• chr11-65717866-A-G
• rs535111
• NM_032193.4:c.*1917T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_032193.4(RNASEH2C):​c.*1917T>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 0.374 in 152,350 control chromosomes in the GnomAD database, including 11,067 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.37 (11047 hom., cov: 31)
  • Exomes 𝑓: 0.34 (20 hom.)
• Consequence: RNASEH2C NM_032193.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.937
• Publications: 14 publications found

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]

KAT5 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder with dysmorphic facies, sleep disturbance, and brain abnormalities

  Inheritance: AD Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 11-65717866-A-G is Benign according to our data. Variant chr11-65717866-A-G is described in ClinVar as Benign. ClinVar VariationId is 305324.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.435 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032193.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RNASEH2C	NM_032193.4	MANE Select	c.*1917T>C		3_prime_UTR	Exon 4 of 4	NP_115569.2
	KAT5	NM_182710.3	MANE Select	c.1265-724A>G		intron	N/A	NP_874369.1
	KAT5	NM_006388.4		c.1166-724A>G		intron	N/A	NP_006379.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RNASEH2C	ENST00000308418.10	TSL:1 MANE Select	c.*1917T>C		3_prime_UTR	Exon 4 of 4	ENSP00000308193.5
	KAT5	ENST00000341318.9	TSL:1 MANE Select	c.1265-724A>G		intron	N/A	ENSP00000340330.4
	KAT5	ENST00000377046.7	TSL:1	c.1166-724A>G		intron	N/A	ENSP00000366245.3

Frequencies

GnomAD3 genomes AF: 0.374 AC: 56822 AN: 151912 Hom.: 11048 Cov.: 31

Gnomad AFR AF: 0.307

Gnomad AMI AF: 0.509

Gnomad AMR AF: 0.340

Gnomad ASJ AF: 0.389

Gnomad EAS AF: 0.297

Gnomad SAS AF: 0.284

Gnomad FIN AF: 0.326

Gnomad MID AF: 0.449

Gnomad NFE AF: 0.439

Gnomad OTH AF: 0.402

GnomAD4 exome AF: 0.340 AC: 108 AN: 318 Hom.: 20 Cov.: 0 AF XY: 0.383 AC XY: 69 AN XY: 180

African (AFR) AF: 0.250 AC: 2 AN: 8

American (AMR) AF: 0.143 AC: 2 AN: 14

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 2 AN: 2

East Asian (EAS) AF: 0.00 AC: 0 AN: 2

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.250 AC: 3 AN: 12

Middle Eastern (MID) AF: 0.500 AC: 1 AN: 2

European-Non Finnish (NFE) AF: 0.352 AC: 93 AN: 264

Other (OTH) AF: 0.357 AC: 5 AN: 14

GnomAD4 genome AF: 0.374 AC: 56860 AN: 152032 Hom.: 11047 Cov.: 31 AF XY: 0.366 AC XY: 27186 AN XY: 74324

African (AFR) AF: 0.307 AC: 12710 AN: 41464

American (AMR) AF: 0.339 AC: 5182 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.389 AC: 1351 AN: 3470

East Asian (EAS) AF: 0.298 AC: 1537 AN: 5166

South Asian (SAS) AF: 0.286 AC: 1378 AN: 4820

European-Finnish (FIN) AF: 0.326 AC: 3446 AN: 10576

Middle Eastern (MID) AF: 0.446 AC: 131 AN: 294

European-Non Finnish (NFE) AF: 0.439 AC: 29818 AN: 67962

Other (OTH) AF: 0.401 AC: 844 AN: 2104

Alfa AF: 0.419 Hom.: 37810

Bravo AF: 0.373

Asia WGS AF: 0.280 AC: 974 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Aicardi-Goutieres syndrome 3 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	3.8
DANN	Benign	0.64
PhyloP100		-0.94
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs535111; hg19: chr11-65485337;