6-13604478-A-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The ENST00000379262.8(SIRT5):c.860A>T(p.His287Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0176 in 1,554,208 control chromosomes in the GnomAD database, including 327 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/14 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as not provided (no stars).

• Frequency:
  • Genomes: 𝑓 0.015 (28 hom., cov: 33)
  • Exomes 𝑓: 0.018 (299 hom.)
• Consequence: SIRT5 ENST00000379262.8 missense, splice_region
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: -1.49

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]

LOC105374938 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0029593408).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0147 (2240/152354) while in subpopulation NFE AF= 0.0202 (1377/68032). AF 95% confidence interval is 0.0194. There are 28 homozygotes in gnomad4. There are 1159 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd at 28 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SIRT5	NM_012241.5	c.857+3529A>T		intron_variant		ENST00000606117.2
LOC105374938	XR_007059460.1	n.2164+1953T>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SIRT5	ENST00000606117.2	c.857+3529A>T		intron_variant		1	NM_012241.5	P1

Frequencies

GnomAD3 genomes AF: 0.0147 AC: 2241 AN: 152236 Hom.: 28 Cov.: 33

Gnomad AFR AF: 0.00311

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.0107

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.0489

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0203

Gnomad OTH AF: 0.0115

GnomAD3 exomes AF: 0.0149 AC: 3656 AN: 245126 Hom.: 53 AF XY: 0.0150 AC XY: 1987 AN XY: 132730

Gnomad AFR exome AF: 0.00200

Gnomad AMR exome AF: 0.00729

Gnomad ASJ exome AF: 0.00241

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00192

Gnomad FIN exome AF: 0.0473

Gnomad NFE exome AF: 0.0195

Gnomad OTH exome AF: 0.0174

GnomAD4 exome AF: 0.0179 AC: 25094 AN: 1401854 Hom.: 299 Cov.: 25 AF XY: 0.0175 AC XY: 12271 AN XY: 700558

Gnomad4 AFR exome AF: 0.00216

Gnomad4 AMR exome AF: 0.00800

Gnomad4 ASJ exome AF: 0.00253

Gnomad4 EAS exome AF: 0.0000255

Gnomad4 SAS exome AF: 0.00243

Gnomad4 FIN exome AF: 0.0490

Gnomad4 NFE exome AF: 0.0197

Gnomad4 OTH exome AF: 0.0153

GnomAD4 genome AF: 0.0147 AC: 2240 AN: 152354 Hom.: 28 Cov.: 33 AF XY: 0.0156 AC XY: 1159 AN XY: 74504

Gnomad4 AFR AF: 0.00310

Gnomad4 AMR AF: 0.0107

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.0489

Gnomad4 NFE AF: 0.0202

Gnomad4 OTH AF: 0.0114

Alfa AF: 0.0155 Hom.: 17

Bravo AF: 0.0111

TwinsUK AF: 0.0208 AC: 77

ALSPAC AF: 0.0148 AC: 57

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.0187 AC: 161

ExAC AF: 0.0149 AC: 1806

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0169

EpiControl AF: 0.0170

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

not provided Other:1

not provided, no classification provided

phenotyping only

GenomeConnect, ClinGen

-

Variant interpretted as Likely benign and reported on 10-30-2014 by Lab or GTR ID 320384. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.68
Cadd	Benign	0.16
Dann	Benign	0.28
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.31	T
MetaRNN	Benign	0.0030	T
MetaSVM	Benign	-0.97	T
MutationTaster	Benign	1.0	N;N;N;N
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.019
Sift	Benign	0.087	T
Sift4G	Benign	0.17	T
Polyphen		0.034	B
Vest4		0.084
ClinPred		0.0017	T
GERP RS		-3.9

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

LitVar

Other links and lift over

dbSNP: rs41273886; hg19: chr6-13604710; COSMIC: COSV63080533;