Genetic Variant ENSG00000310566:n.470+950G>C (chr12-120291724-C-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The ENST00000850922.1(ENSG00000310566):n.470+950G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.688 in 151,914 control chromosomes in the GnomAD database, including 36,258 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.69 ( 36256 hom., cov: 31)

Exomes 𝑓: 0.83 ( 2 hom. )

Consequence

ENSG00000310566
ENST00000850922.1 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.253

Publications

3 publications found

Variant links:

Genes affected

ENSG00000310566 (HGNC:):

ENSG00000310566 links:

RNU4-2 (HGNC:10193): (RNA, U4 small nuclear 2)

RNU4-2 links:

SIRT4 (HGNC:14932): (sirtuin 4) This gene encodes a member of the sirtuin family of proteins, homologs to the yeast Sir2 protein. Members of the sirtuin family are characterized by a sirtuin core domain and grouped into four classes. The functions of human sirtuins have not yet been determined; however, yeast sirtuin proteins are known to regulate epigenetic gene silencing and suppress recombination of rDNA. Studies suggest that the human sirtuins may function as intracellular regulatory proteins with mono-ADP-ribosyltransferase activity. The protein encoded by this gene is included in class IV of the sirtuin family. [provided by RefSeq, Jul 2008]

SIRT4 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.79).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.875 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RNU4-2	NR_003137.3 link	n.*35G>C		downstream_gene_variant		ENST00000365668.2
SIRT4	XM_006719309.5 link	c.-1572C>G		upstream_gene_variant			XP_006719372.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE
ENSG00000310566	ENST00000850922.1 link	n.470+950G>C	intron_variant	Intron 2 of 5
ENSG00000310566	ENST00000850923.1 link	n.358+1156G>C	intron_variant	Intron 1 of 2
ENSG00000310566	ENST00000850924.1 link	n.358+1156G>C	intron_variant	Intron 1 of 2
RNU4-2	ENST00000365668.2 link	n.*35G>C	downstream_gene_variant		6	NR_003137.3

Frequencies

GnomAD3 genomes

AF:

0.688

AC:

104384

AN:

151790

Hom.:

36234

Cov.:

show subpopulations

Gnomad AFR

AF:

0.642

Gnomad AMI

AF:

0.834

Gnomad AMR

AF:

0.639

Gnomad ASJ

AF:

0.549

Gnomad EAS

AF:

0.896

Gnomad SAS

AF:

0.808

Gnomad FIN

AF:

0.736

Gnomad MID

AF:

0.655

Gnomad NFE

AF:

0.699

Gnomad OTH

AF:

0.698

GnomAD4 exome

AF:

0.833

AC:

AN:

Hom.:

Cov.:

AF XY:

1.00

AC XY:

AN XY:

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

1.00

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.750

AC:

AN:

Other (OTH)

AC:

AN:

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Hom

Variant carriers

<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:

0.688

AC:

104456

AN:

151908

Hom.:

36256

Cov.:

AF XY:

0.690

AC XY:

51243

AN XY:

74264

show subpopulations

African (AFR)

AF:

0.642

AC:

26538

AN:

41330

American (AMR)

AF:

0.639

AC:

9742

AN:

15248

Ashkenazi Jewish (ASJ)

AF:

0.549

AC:

1905

AN:

3472

East Asian (EAS)

AF:

0.896

AC:

4642

AN:

5180

South Asian (SAS)

AF:

0.809

AC:

3906

AN:

4826

European-Finnish (FIN)

AF:

0.736

AC:

7789

AN:

10578

Middle Eastern (MID)

AF:

0.643

AC:

189

AN:

294

European-Non Finnish (NFE)

AF:

0.699

AC:

47508

AN:

67966

Other (OTH)

AF:

0.703

AC:

1481

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1626

3252

4878

6504

8130

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

822

1644

2466

3288

4110

<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:

0.602

Hom.:

1705

Bravo

AF:

0.679

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

0.032

(source)

DANN

Benign

0.14

PhyloP100

-0.25

Mutation Taster

=99/1

polymorphism

(source)

Splicing

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

Computational scores

Splicing

Publications

Other links and lift over