chr11-65718251-C-T

Variant names:

• chr11-65718251-C-T
• rs376966597
• NM_032193.4:c.*1532G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS1

The NM_032193.4(RNASEH2C):​c.*1532G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000891 in 235,600 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000084 (0 hom.)
• Consequence: RNASEH2C NM_032193.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.218
• Publications: 0 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000092 (14/152224) while in subpopulation EAS AF = 0.00155 (8/5178). AF 95% confidence interval is 0.000768. There are 0 homozygotes in GnomAd4. There are 6 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.*1532G>A		3_prime_UTR	Exon 4 of 4	NP_115569.2
	KAT5	NM_182710.3	MANE Select	c.1265-339C>T		intron	N/A	NP_874369.1	Q92993-3
	KAT5	NM_006388.4		c.1166-339C>T		intron	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.*1532G>A		3_prime_UTR	Exon 4 of 4	ENSP00000308193.5	Q8TDP1
	KAT5	ENST00000341318.9	TSL:1 MANE Select	c.1265-339C>T		intron	N/A	ENSP00000340330.4	Q92993-3
	KAT5	ENST00000377046.7	TSL:1	c.1166-339C>T		intron	N/A	ENSP00000366245.3	Q92993-1

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152106 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: 0.00154

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000840 AC: 7 AN: 83376 Hom.: 0 Cov.: 0 AF XY: 0.0000230 AC XY: 1 AN XY: 43496

African (AFR) AF: 0.00 AC: 0 AN: 2936

American (AMR) AF: 0.00 AC: 0 AN: 4590

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2492

East Asian (EAS) AF: 0.000895 AC: 5 AN: 5586

South Asian (SAS) AF: 0.00 AC: 0 AN: 8042

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 3310

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 326

European-Non Finnish (NFE) AF: 0.0000389 AC: 2 AN: 51368

Other (OTH) AF: 0.00 AC: 0 AN: 4726

GnomAD4 genome AF: 0.0000920 AC: 14 AN: 152224 Hom.: 0 Cov.: 32 AF XY: 0.0000806 AC XY: 6 AN XY: 74440

African (AFR) AF: 0.00 AC: 0 AN: 41512

American (AMR) AF: 0.00 AC: 0 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00154 AC: 8 AN: 5178

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68006

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000106

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
BayesDel_noAF	Benign	-0.91
CADD	Benign	13
DANN	Benign	0.45
PhyloP100		0.22
PromoterAI		0.020	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.18		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: rs376966597; hg19: chr11-65485722;