chr11-65716981-CAGTG-C

Variant names:

• chr11-65716981-CAGTG-C
• rs781459819
• NM_182710.3:c.1264+3_1264+6delGAGT

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP3 BS2

The NM_182710.3(KAT5):​c.1264+3_1264+6delGAGT variant causes a splice region, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,612,044 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: KAT5 NM_182710.3 splice_region, intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 10.0

Genes affected

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]

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]

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 2: max_spliceai, phyloP100way_vertebrate [when was below the threshold]
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KAT5	NM_182710.3	c.1264+3_1264+6delGAGT		splice_region_variant, intron_variant	Intron 10 of 12	ENST00000341318.9	NP_874369.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KAT5	ENST00000341318.9	c.1264+3_1264+6delGAGT		splice_region_variant, intron_variant	Intron 10 of 12	1	NM_182710.3	ENSP00000340330.4

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152236 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251448 AF XY: 0.0000221

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000343 AC: 5 AN: 1459808 Hom.: 0 AF XY: 0.00000688 AC XY: 5 AN XY: 726354

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 33434

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 44724

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26130

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39688

Gnomad4 SAS exome AF: 0.0000348 AC: 3 AN: 86212

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53418

Gnomad4 NFE exome AF: 9.01e-7 AC: 1 AN: 1110098

Gnomad4 Remaining exome AF: 0.0000166 AC: 1 AN: 60340

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152236 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74382

Gnomad4 AFR AF: 0.00 AC: 0 AN: 0

Gnomad4 AMR AF: 0.00 AC: 0 AN: 0

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.000192 AC: 0.000192086 AN: 0.000192086

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.00 AC: 0 AN: 0

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Neurodevelopmental disorder with dysmorphic facies, sleep disturbance, and brain abnormalities Uncertain:1

Jun 29, 2021

Breda Genetics srl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on allele frequency, in-silico prediction scores and a certain overlap with the clinical phenotype, we interpreted this variant at least as of uncertain significance. The lack of one or more of the following features has discouraged further investigations: lack of a possible second hit in autosomal recessive conditions, presence of healthy controls in databases for autosomal dominant conditions, presence of unmatching cardinal clinical features in the patient or in the known gene-disease association, and/or variant type outside the known gene mutational spectrum. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Mutation Taster		=38/162	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.60		Position offset: -4
DS_DL_spliceai		1.0		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs781459819; hg19: chr11-65484452;