rs139054969

Variant names:

• chr12-56273097-G-A
• rs139054969
• NM_004077.3:c.1388C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_004077.3(CS):​c.1388C>T​(p.Ser463Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00203 in 1,609,866 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (7 hom.)
• Consequence: CS NM_004077.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 4.36
• Publications: 2 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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.014113903).
• BP6: Variant 12-56273097-G-A is Benign according to our data. Variant chr12-56273097-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 708211.
• BS2: High AC in GnomAd4 at 225 AD gene.

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.1388C>T	p.Ser463Phe	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.1388C>T	p.Ser463Phe	missense	Exon 11 of 11	ENSP00000342056.3	O75390
	CS	ENST00000548567.5	TSL:1	c.1190C>T	p.Ser397Phe	missense	Exon 12 of 12	ENSP00000446779.1	A0A0C4DGI3
	CS	ENST00000904225.1		c.1352C>T	p.Ser451Phe	missense	Exon 11 of 11	ENSP00000574284.1

Frequencies

GnomAD3 genomes AF: 0.00149 AC: 226 AN: 152118 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000459

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000852

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00262

Gnomad OTH AF: 0.00383

GnomAD2 exomes AF: 0.00149 AC: 365 AN: 245748 AF XY: 0.00163

Gnomad AFR exome AF: 0.000618

Gnomad AMR exome AF: 0.000422

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00102

Gnomad NFE exome AF: 0.00234

Gnomad OTH exome AF: 0.000833

GnomAD4 exome AF: 0.00209 AC: 3050 AN: 1457630 Hom.: 7 Cov.: 31 AF XY: 0.00212 AC XY: 1536 AN XY: 724892

African (AFR) AF: 0.000330 AC: 11 AN: 33310

American (AMR) AF: 0.000526 AC: 23 AN: 43736

Ashkenazi Jewish (ASJ) AF: 0.0000386 AC: 1 AN: 25920

East Asian (EAS) AF: 0.00 AC: 0 AN: 39654

South Asian (SAS) AF: 0.00176 AC: 150 AN: 85408

European-Finnish (FIN) AF: 0.000824 AC: 44 AN: 53400

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5732

European-Non Finnish (NFE) AF: 0.00245 AC: 2719 AN: 1110252

Other (OTH) AF: 0.00168 AC: 101 AN: 60218

GnomAD4 genome AF: 0.00148 AC: 225 AN: 152236 Hom.: 0 Cov.: 32 AF XY: 0.00132 AC XY: 98 AN XY: 74418

African (AFR) AF: 0.000457 AC: 19 AN: 41544

American (AMR) AF: 0.000850 AC: 13 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4816

European-Finnish (FIN) AF: 0.000471 AC: 5 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00262 AC: 178 AN: 68016

Other (OTH) AF: 0.00379 AC: 8 AN: 2112

Alfa AF: 0.00175 Hom.: 0

Bravo AF: 0.00138

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00267 AC: 23

ExAC AF: 0.00143 AC: 173

EpiCase AF: 0.00240

EpiControl AF: 0.00243

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.50	D
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.0020	T
MetaRNN	Benign	0.014	T
MetaSVM	Benign	-0.76	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		4.4
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.10
Sift	Benign	0.12	T
Sift4G	Uncertain	0.021	D
Polyphen		0.60	P
Vest4		0.12
MVP		0.36
MPC		1.3
ClinPred		0.029	T
GERP RS		5.1
Varity_R		0.41
gMVP		0.50
Mutation Taster		=92/8	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: rs139054969; hg19: chr12-56666881; COSMIC: COSV100370080; COSMIC: COSV100370080;