Genetic Variant SIRT5:c.249+1177G>C (chr6-13589641-G-C) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The NM_012241.5(SIRT5):c.249+1177G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.189 in 152,322 control chromosomes in the GnomAD database, including 2,953 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 0.19 ( 2951 hom., cov: 32)

Exomes 𝑓: 0.16 ( 2 hom. )

Consequence

SIRT5
NM_012241.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.07

Publications

5 publications found

Variant links:

Genes affected

SIRT5 (HGNC:14933): (sirtuin 5) 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 III of the sirtuin family. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Jul 2010]

SIRT5 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=-0.84).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.413 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012241.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
SIRT5	NM_012241.5	MANE Select	c.249+1177G>C	intron	N/A	NP_036373.1
SIRT5	NM_001376798.1		c.249+1177G>C	intron	N/A	NP_001363727.1
SIRT5	NM_001376799.1		c.249+1177G>C	intron	N/A	NP_001363728.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
SIRT5	ENST00000606117.2	TSL:1 MANE Select	c.249+1177G>C	intron	N/A	ENSP00000476228.1
SIRT5	ENST00000397350.7	TSL:1	c.249+1177G>C	intron	N/A	ENSP00000380509.3
SIRT5	ENST00000379262.8	TSL:1	c.249+1177G>C	intron	N/A	ENSP00000368564.4

Frequencies

GnomAD3 genomes

AF:

0.189

AC:

28799

AN:

152004

Hom.:

2948

Cov.:

show subpopulations

Gnomad AFR

AF:

0.148

Gnomad AMI

AF:

0.111

Gnomad AMR

AF:

0.176

Gnomad ASJ

AF:

0.204

Gnomad EAS

AF:

0.428

Gnomad SAS

AF:

0.142

Gnomad FIN

AF:

0.221

Gnomad MID

AF:

0.250

Gnomad NFE

AF:

0.197

Gnomad OTH

AF:

0.212

GnomAD4 exome

AF:

0.160

AC:

AN:

200

Hom.:

AF XY:

0.120

AC XY:

AN XY:

142

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.500

AC:

AN:

East Asian (EAS)

AF:

0.250

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

0.208

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.147

AC:

AN:

150

Other (OTH)

AF:

0.188

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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:

0.189

AC:

28810

AN:

152122

Hom.:

2951

Cov.:

AF XY:

0.190

AC XY:

14113

AN XY:

74360

show subpopulations

African (AFR)

AF:

0.148

AC:

6144

AN:

41500

American (AMR)

AF:

0.176

AC:

2687

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.204

AC:

707

AN:

3468

East Asian (EAS)

AF:

0.428

AC:

2208

AN:

5160

South Asian (SAS)

AF:

0.141

AC:

680

AN:

4824

European-Finnish (FIN)

AF:

0.221

AC:

2343

AN:

10590

Middle Eastern (MID)

AF:

0.252

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.197

AC:

13415

AN:

67980

Other (OTH)

AF:

0.214

AC:

451

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1186

2371

3557

4742

5928

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

308

616

924

1232

1540

<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:

0.0965

Hom.:

145

Bravo

AF:

0.188

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

2.4

(source)

DANN

Benign

0.28

PhyloP100

1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over