NM_004077.3:c.1250T>C

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M417K) has been classified as Uncertain significance.

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

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

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.1250T>C	p.Met417Thr	missense	Exon 11 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.1250T>C	p.Met417Thr	missense	Exon 11 of 11	ENSP00000342056.3	O75390
	CS	ENST00000548567.5	TSL:1	c.1052T>C	p.Met351Thr	missense	Exon 12 of 12	ENSP00000446779.1	A0A0C4DGI3
	CS	ENST00000904225.1		c.1214T>C	p.Met405Thr	missense	Exon 11 of 11	ENSP00000574284.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Benign	0.0038	T
MetaRNN	Pathogenic	0.76	D
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.7	L
PhyloP100		8.4
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-4.5	D
REVEL	Uncertain	0.44
Sift	Benign	0.51	T
Sift4G	Benign	0.40	T
Polyphen		0.51	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
Mutation Taster		=1/99	disease causing

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: rs774054252; hg19: chr12-56667019;