Variant 12-56273097-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

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

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 4.36

Variant links:

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]

CS links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 708211.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

BS2

High AC in GnomAd4 at 225 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CS	NM_004077.3 linkuse as main transcript	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 linkuse as main transcript	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.:

Cov.:

show subpopulations

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.:

AF XY:

0.00163

AC XY:

217

AN XY:

132804

show subpopulations

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.:

Cov.:

AF XY:

0.00212

AC XY:

1536

AN XY:

724892

show subpopulations

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.:

Cov.:

AF XY:

0.00132

AC XY:

AN XY:

74418

show subpopulations

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.:

Bravo

AF:

0.00138

TwinsUK

AF:

0.00297

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00267

AC:

ExAC

AF:

0.00143

AC:

173

EpiCase

AF:

0.00240

EpiControl

AF:

0.00243

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

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

Labcorp Genetics (formerly Invitae), Labcorp

Jul 06, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.25

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.50

.;D;.

Eigen

Uncertain

0.25

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.75

T;T;T

M_CAP

Benign

0.0020

MetaRNN

Benign

0.014

T;T;T

MetaSVM

Benign

-0.76

MutationAssessor

Uncertain

2.3

.;M;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.51

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over