12-56273235-A-G

Variant names:

• chr12-56273235-A-G
• rs774054252
• NM_004077.3:c.1250T>C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_004077.3(CS):​c.1250T>C​(p.Met417Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CS NM_004077.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.43

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

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.762

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CS	NM_004077.3	c.1250T>C	p.Met417Thr	missense_variant	Exon 11 of 11	ENST00000351328.8	NP_004068.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CS	ENST00000351328.8	c.1250T>C	p.Met417Thr	missense_variant	Exon 11 of 11	1	NM_004077.3	ENSP00000342056.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Uncertain	23
DANN	Benign	0.88
DEOGEN2	Uncertain	0.52	.;D;.;.
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.97	D;D;D;D
M_CAP	Benign	0.0038	T
MetaRNN	Pathogenic	0.76	D;D;D;D
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.7	.;L;.;.
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-4.5	D;D;D;D
REVEL	Uncertain	0.44
Sift	Benign	0.51	T;T;T;T
Sift4G	Benign	0.40	T;T;T;T
Polyphen		0.51	.;P;.;P
Vest4		0.78
MutPred		0.38		.;Gain of catalytic residue at M417 (P = 0);.;.;
MVP		0.79
MPC		1.8
ClinPred		0.85	D
GERP RS		5.3
Varity_R		0.60
gMVP		0.83

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: rs774054252; hg19: chr12-56667019;