12-56273097-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2 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

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 Benign. Variant got -8 ACMG points.

• PP2: Missense variant where missense usually causes diseases, CS
• 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 id is 708211.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS2: High AC in GnomAd at 226 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CS	NM_004077.3	c.1388C>T	p.Ser463Phe	missense_variant	11/11	ENST00000351328.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CS	ENST00000351328.8	c.1388C>T	p.Ser463Phe	missense_variant	11/11	1	NM_004077.3	P1

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

GnomAD3 exomes AF: 0.00149 AC: 365 AN: 245748 Hom.: 1 AF XY: 0.00163 AC XY: 217 AN XY: 132804

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 SAS exome AF: 0.00183

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

Gnomad4 AFR exome AF: 0.000330

Gnomad4 AMR exome AF: 0.000526

Gnomad4 ASJ exome AF: 0.0000386

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00176

Gnomad4 FIN exome AF: 0.000824

Gnomad4 NFE exome AF: 0.00245

Gnomad4 OTH exome AF: 0.00168

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

Gnomad4 AFR AF: 0.000457

Gnomad4 AMR AF: 0.000850

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.00262

Gnomad4 OTH AF: 0.00379

Alfa AF: 0.00214 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

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 03, 2022

The c.1388C>T (p.S463F) alteration is located in exon 11 (coding exon 11) of the CS gene. This alteration results from a C to T substitution at nucleotide position 1388, causing the serine (S) at amino acid position 463 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jul 06, 2018

- -

Computational scores

Source: dbNSFP v4.3

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
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.75	T;T;T
M_CAP	Benign	0.0020	T
MetaRNN	Benign	0.014	T;T;T
MetaSVM	Benign	-0.76	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-2.8	D;D;D
REVEL	Benign	0.10
Sift	Benign	0.12	T;D;D
Sift4G	Uncertain	0.021	D;D;D
Polyphen		0.60, 0.37	.;P;B
Vest4		0.12
MVP		0.36
MPC		1.3
ClinPred		0.029	T
GERP RS		5.1
Varity_R		0.41
gMVP		0.50

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: rs139054969; hg19: chr12-56666881; COSMIC: COSV100370080; COSMIC: COSV100370080;