11-65719800-G-T

Variant names:

• chr11-65719800-G-T
• rs771013055
• NM_032193.4:c.478C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_032193.4(RNASEH2C):​c.478C>A​(p.Gln160Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,461,864 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: RNASEH2C NM_032193.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.56
• Publications: 1 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.09122008).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RNASEH2C	NM_032193.4	MANE Select	c.478C>A	p.Gln160Lys	missense	Exon 4 of 4	NP_115569.2
	KAT5	NM_182710.3	MANE Select	c.*619G>T		downstream_gene	N/A	NP_874369.1	Q92993-3
	KAT5	NM_006388.4		c.*619G>T		downstream_gene	N/A	NP_006379.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RNASEH2C	ENST00000308418.10	TSL:1 MANE Select	c.478C>A	p.Gln160Lys	missense	Exon 4 of 4	ENSP00000308193.5	Q8TDP1
	RNASEH2C	ENST00000527610.1	TSL:2	c.713C>A	p.Thr238Lys	missense	Exon 3 of 3	ENSP00000432897.1	E9PN81
	RNASEH2C	ENST00000886953.1		c.496C>A	p.Gln166Lys	missense	Exon 4 of 4	ENSP00000557012.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000199 AC: 5 AN: 251378 AF XY: 0.00000736

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: 0.0000440

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000130 AC: 19 AN: 1461864 Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7 AN XY: 727232

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000162 AC: 18 AN: 1112002

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Aicardi-Goutieres syndrome 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.078	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	20
DANN	Benign	0.95
DEOGEN2	Benign	0.025	T
Eigen	Benign	-0.018
Eigen_PC	Benign	0.013
FATHMM_MKL	Benign	0.28	N
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.091	T
MetaSVM	Uncertain	-0.063	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		2.6
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.86	N
REVEL	Benign	0.19
Sift	Benign	0.25	T
Sift4G	Benign	0.15	T
Polyphen		0.20	B
Vest4		0.081
MutPred		0.36		Gain of methylation at Q160 (P = 0.0049)
MVP		0.55
MPC		0.55
ClinPred		0.19	T
GERP RS		4.0
Varity_R		0.38
gMVP		0.49
Mutation Taster		=93/7	polymorphism

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

Other links and lift over

dbSNP: rs771013055; hg19: chr11-65487271;