chr12-120312436-A-G

Variant names:

• chr12-120312436-A-G
• rs2261612
• NM_012240.3:c.498-20A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000202967.4(SIRT4):​c.498-20A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.71 in 1,588,520 control chromosomes in the GnomAD database, including 403,213 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. There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.71 (38534 hom., cov: 32)
  • Exomes 𝑓: 0.71 (364679 hom.)
• Consequence: SIRT4 ENST00000202967.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0250
• Publications: 20 publications found

Genes affected

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]

ENSG00000298788 (HGNC:):

ACMG classification

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

• BP4: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 2 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.723 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000202967.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIRT4	NM_012240.3	MANE Select	c.498-20A>G		intron	N/A	NP_036372.1
	SIRT4	NM_001385733.2		c.498-20A>G		intron	N/A	NP_001372662.1
	SIRT4	NM_001385734.1		c.225-20A>G		intron	N/A	NP_001372663.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIRT4	ENST00000202967.4	TSL:1 MANE Select	c.498-20A>G		intron	N/A	ENSP00000202967.4
	SIRT4	ENST00000850925.1		c.225-20A>G		intron	N/A	ENSP00000521005.1
	SIRT4	ENST00000537892.1	TSL:5	n.180-148A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.709 AC: 107809 AN: 151956 Hom.: 38512 Cov.: 32

Gnomad AFR AF: 0.724

Gnomad AMI AF: 0.796

Gnomad AMR AF: 0.734

Gnomad ASJ AF: 0.592

Gnomad EAS AF: 0.477

Gnomad SAS AF: 0.740

Gnomad FIN AF: 0.710

Gnomad MID AF: 0.725

Gnomad NFE AF: 0.715

Gnomad OTH AF: 0.715

GnomAD2 exomes AF: 0.702 AC: 163810 AN: 233376 AF XY: 0.704

Gnomad AFR exome AF: 0.727

Gnomad AMR exome AF: 0.747

Gnomad ASJ exome AF: 0.601

Gnomad EAS exome AF: 0.463

Gnomad FIN exome AF: 0.710

Gnomad NFE exome AF: 0.719

Gnomad OTH exome AF: 0.708

GnomAD4 exome AF: 0.711 AC: 1020692 AN: 1436446 Hom.: 364679 Cov.: 39 AF XY: 0.711 AC XY: 506944 AN XY: 712724

African (AFR) AF: 0.727 AC: 23477 AN: 32302

American (AMR) AF: 0.748 AC: 30246 AN: 40450

Ashkenazi Jewish (ASJ) AF: 0.606 AC: 14904 AN: 24612

East Asian (EAS) AF: 0.466 AC: 18390 AN: 39422

South Asian (SAS) AF: 0.744 AC: 61892 AN: 83240

European-Finnish (FIN) AF: 0.714 AC: 37533 AN: 52594

Middle Eastern (MID) AF: 0.715 AC: 3734 AN: 5222

European-Non Finnish (NFE) AF: 0.718 AC: 788934 AN: 1099452

Other (OTH) AF: 0.703 AC: 41582 AN: 59152

GnomAD4 genome AF: 0.709 AC: 107890 AN: 152074 Hom.: 38534 Cov.: 32 AF XY: 0.706 AC XY: 52481 AN XY: 74330

African (AFR) AF: 0.724 AC: 30038 AN: 41482

American (AMR) AF: 0.734 AC: 11208 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.592 AC: 2054 AN: 3470

East Asian (EAS) AF: 0.477 AC: 2463 AN: 5166

South Asian (SAS) AF: 0.740 AC: 3567 AN: 4822

European-Finnish (FIN) AF: 0.710 AC: 7516 AN: 10580

Middle Eastern (MID) AF: 0.731 AC: 215 AN: 294

European-Non Finnish (NFE) AF: 0.715 AC: 48588 AN: 67968

Other (OTH) AF: 0.718 AC: 1515 AN: 2110

Alfa AF: 0.711 Hom.: 66657

Bravo AF: 0.712

Asia WGS AF: 0.683 AC: 2373 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.9
DANN	Benign	0.15
PhyloP100		-0.025
BranchPoint Hunter		2.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs2261612; hg19: chr12-120750239; COSMIC: COSV52541841; COSMIC: COSV52541841;