11-65718256-T-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_032193.4(RNASEH2C):c.*1527A>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 0.885 in 231,548 control chromosomes in the GnomAD database, including 91,111 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.88 ( 59041 hom., cov: 32)

Exomes 𝑓: 0.90 ( 32070 hom. )

Consequence

RNASEH2C
NM_032193.4 3_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.452

Publications

11 publications found

Variant links:

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]

RNASEH2C links:

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)

KAT5 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BP6

Variant 11-65718256-T-G is Benign according to our data. Variant chr11-65718256-T-G is described in ClinVar as Benign. ClinVar VariationId is 305334.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.91 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RNASEH2C	NM_032193.4 link	c.*1527A>C		3_prime_UTR_variant	Exon 4 of 4	ENST00000308418.10	NP_115569.2
KAT5	NM_182710.3 link	c.1265-334T>G		intron_variant	Intron 10 of 12	ENST00000341318.9	NP_874369.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RNASEH2C	ENST00000308418.10 link	c.*1527A>C		3_prime_UTR_variant	Exon 4 of 4	1	NM_032193.4	ENSP00000308193.5
KAT5	ENST00000341318.9 link	c.1265-334T>G		intron_variant	Intron 10 of 12	1	NM_182710.3	ENSP00000340330.4

Frequencies

GnomAD3 genomes

AF:

0.879

AC:

133747

AN:

152074

Hom.:

58993

Cov.:

show subpopulations

Gnomad AFR

AF:

0.830

Gnomad AMI

AF:

0.846

Gnomad AMR

AF:

0.879

Gnomad ASJ

AF:

0.895

Gnomad EAS

AF:

0.894

Gnomad SAS

AF:

0.719

Gnomad FIN

AF:

0.902

Gnomad MID

AF:

0.877

Gnomad NFE

AF:

0.916

Gnomad OTH

AF:

0.880

GnomAD4 exome

AF:

0.896

AC:

71105

AN:

79356

Hom.:

32070

Cov.:

AF XY:

0.890

AC XY:

36685

AN XY:

41196

show subpopulations

African (AFR)

AF:

0.823

AC:

2271

AN:

2758

American (AMR)

AF:

0.878

AC:

4042

AN:

4606

Ashkenazi Jewish (ASJ)

AF:

0.887

AC:

2246

AN:

2532

East Asian (EAS)

AF:

0.901

AC:

4898

AN:

5438

South Asian (SAS)

AF:

0.740

AC:

5127

AN:

6930

European-Finnish (FIN)

AF:

0.913

AC:

2973

AN:

3258

Middle Eastern (MID)

AF:

0.909

AC:

269

AN:

296

European-Non Finnish (NFE)

AF:

0.922

AC:

45126

AN:

48938

Other (OTH)

AF:

0.903

AC:

4153

AN:

4600

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.514

Heterozygous variant carriers

350

700

1050

1400

1750

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

326

652

978

1304

1630

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.880

AC:

133856

AN:

152192

Hom.:

59041

Cov.:

AF XY:

0.877

AC XY:

65257

AN XY:

74398

show subpopulations

African (AFR)

AF:

0.830

AC:

34419

AN:

41486

American (AMR)

AF:

0.880

AC:

13453

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.895

AC:

3109

AN:

3472

East Asian (EAS)

AF:

0.894

AC:

4624

AN:

5172

South Asian (SAS)

AF:

0.720

AC:

3472

AN:

4822

European-Finnish (FIN)

AF:

0.902

AC:

9568

AN:

10602

Middle Eastern (MID)

AF:

0.871

AC:

256

AN:

294

European-Non Finnish (NFE)

AF:

0.916

AC:

62328

AN:

68026

Other (OTH)

AF:

0.878

AC:

1855

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

Heterozygous variant carriers

837

1674

2510

3347

4184

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

898

1796

2694

3592

4490

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.904

Hom.:

235547

Bravo

AF:

0.878

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Aicardi-Goutieres syndrome 3

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

1.2

(source)

DANN

Benign

0.65

PhyloP100

-0.45

PromoterAI

0.0027

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over