12-56283855-C-T

Variant names:

• chr12-56283855-C-T
• rs561428964
• NM_004077.3:c.204G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004077.3(CS):​c.204G>A​(p.Met68Ile) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000034 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CS NM_004077.3 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.29
• Publications: 0 publications found

Genes affected

CS (HGNC:2422): (citrate synthase) The protein encoded by this gene is a Krebs tricarboxylic acid cycle enzyme that catalyzes the synthesis of citrate from oxaloacetate and acetyl coenzyme A. The enzyme is found in nearly all cells capable of oxidative metablism. This protein is nuclear encoded and transported into the mitochondrial matrix, where the mature form is found. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22366795).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004077.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CS	NM_004077.3	MANE Select	c.204G>A	p.Met68Ile	missense splice_region	Exon 4 of 11	NP_004068.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CS	ENST00000351328.8	TSL:1 MANE Select	c.204G>A	p.Met68Ile	missense splice_region	Exon 4 of 11	ENSP00000342056.3	O75390
	CS	ENST00000548567.5	TSL:1	c.6G>A	p.Met2Ile	missense splice_region	Exon 5 of 12	ENSP00000446779.1	A0A0C4DGI3
	CS	ENST00000904225.1		c.204G>A	p.Met68Ile	missense splice_region	Exon 4 of 11	ENSP00000574284.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000799 AC: 2 AN: 250450 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000343 AC: 5 AN: 1457566 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 725314

African (AFR) AF: 0.00 AC: 0 AN: 33376

American (AMR) AF: 0.0000224 AC: 1 AN: 44674

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26054

East Asian (EAS) AF: 0.00 AC: 0 AN: 39652

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86046

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53358

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1108438

Other (OTH) AF: 0.00 AC: 0 AN: 60210

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	22
DANN	Benign	0.96
DEOGEN2	Benign	0.20	T
Eigen	Benign	-0.19
Eigen_PC	Benign	0.0054
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.0043	T
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L
PhyloP100		1.3
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.94	N
REVEL	Benign	0.081
Sift	Benign	0.28	T
Sift4G	Benign	0.30	T
Polyphen		0.0	B
Vest4		0.20
MutPred		0.40		Gain of catalytic residue at D66 (P = 0)
MVP		0.33
MPC		1.3
ClinPred		0.27	T
GERP RS		4.7
Varity_R		0.47
gMVP		0.60
Mutation Taster		=73/27	polymorphism

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

Other links and lift over

dbSNP: rs561428964; hg19: chr12-56677639;