rs231775

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_005214.5(CTLA4):c.49A>G(p.Thr17Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.394 in 1,613,082 control chromosomes in the GnomAD database, including 128,827 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.40 ( 12592 hom., cov: 32)

Exomes 𝑓: 0.39 ( 116235 hom. )

Consequence

CTLA4
NM_005214.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4O:6

Conservation

PhyloP100: -0.309

Variant links:

Genes affected

CTLA4 (HGNC:2505): (cytotoxic T-lymphocyte associated protein 4) This gene is a member of the immunoglobulin superfamily and encodes a protein which transmits an inhibitory signal to T cells. The protein contains a V domain, a transmembrane domain, and a cytoplasmic tail. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. The membrane-bound isoform functions as a homodimer interconnected by a disulfide bond, while the soluble isoform functions as a monomer. Mutations in this gene have been associated with insulin-dependent diabetes mellitus, Graves disease, Hashimoto thyroiditis, celiac disease, systemic lupus erythematosus, thyroid-associated orbitopathy, and other autoimmune diseases. [provided by RefSeq, Jul 2008]

CTLA4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=2.511961E-5).

BP6

Variant 2-203867991-A-G is Benign according to our data. Variant chr2-203867991-A-G is described in ClinVar as [Benign]. Clinvar id is 16921.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-203867991-A-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.626 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CTLA4	NM_005214.5 linkuse as main transcript	c.49A>G	p.Thr17Ala	missense_variant	1/4	ENST00000648405.2	NP_005205.2
CTLA4	NM_001037631.3 linkuse as main transcript	c.49A>G	p.Thr17Ala	missense_variant	1/3		NP_001032720.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CTLA4	ENST00000648405.2 linkuse as main transcript	c.49A>G	p.Thr17Ala	missense_variant	1/4		NM_005214.5	ENSP00000497102	P1	P16410-1

Frequencies

GnomAD3 genomes

AF:

0.400

AC:

60714

AN:

151936

Hom.:

12575

Cov.:

show subpopulations

Gnomad AFR

AF:

0.374

Gnomad AMI

AF:

0.429

Gnomad AMR

AF:

0.412

Gnomad ASJ

AF:

0.300

Gnomad EAS

AF:

0.645

Gnomad SAS

AF:

0.320

Gnomad FIN

AF:

0.530

Gnomad MID

AF:

0.277

Gnomad NFE

AF:

0.386

Gnomad OTH

AF:

0.359

GnomAD3 exomes

AF:

0.415

AC:

104287

AN:

251236

Hom.:

22926

AF XY:

0.406

AC XY:

55192

AN XY:

135776

show subpopulations

Gnomad AFR exome

AF:

0.374

Gnomad AMR exome

AF:

0.462

Gnomad ASJ exome

AF:

0.302

Gnomad EAS exome

AF:

0.666

Gnomad SAS exome

AF:

0.319

Gnomad FIN exome

AF:

0.528

Gnomad NFE exome

AF:

0.382

Gnomad OTH exome

AF:

0.390

GnomAD4 exome

AF:

0.393

AC:

573983

AN:

1461028

Hom.:

116235

Cov.:

AF XY:

0.390

AC XY:

283226

AN XY:

726866

show subpopulations

Gnomad4 AFR exome

AF:

0.378

Gnomad4 AMR exome

AF:

0.454

Gnomad4 ASJ exome

AF:

0.302

Gnomad4 EAS exome

AF:

0.645

Gnomad4 SAS exome

AF:

0.321

Gnomad4 FIN exome

AF:

0.529

Gnomad4 NFE exome

AF:

0.384

Gnomad4 OTH exome

AF:

0.391

GnomAD4 genome

AF:

0.400

AC:

60776

AN:

152054

Hom.:

12592

Cov.:

AF XY:

0.407

AC XY:

30216

AN XY:

74324

show subpopulations

Gnomad4 AFR

AF:

0.374

Gnomad4 AMR

AF:

0.412

Gnomad4 ASJ

AF:

0.300

Gnomad4 EAS

AF:

0.644

Gnomad4 SAS

AF:

0.321

Gnomad4 FIN

AF:

0.530

Gnomad4 NFE

AF:

0.386

Gnomad4 OTH

AF:

0.358

Alfa

AF:

0.372

Hom.:

22683

Bravo

AF:

0.394

TwinsUK

AF:

0.372

AC:

1381

ALSPAC

AF:

0.381

AC:

1467

ESP6500AA

AF:

0.370

AC:

1629

ESP6500EA

AF:

0.369

AC:

3176

ExAC

AF:

0.411

AC:

49919

Asia WGS

AF:

0.445

AC:

1543

AN:

3476

EpiCase

AF:

0.358

EpiControl

AF:

0.349

ClinVar

Significance: Benign

Submissions summary: Benign:4Other:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2Other:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2018	This variant is associated with the following publications: (PMID: 19737153, 19037649, 22497911, 20920330, 21387262, 18757416, 23830732, 21503616, 21612409, 22011251, 19884265, 20145677, 11426323, 21453059, 22905924, 20538028, 23246583, 19922464, 11976786, 12417883, 22699762, 21346773, 21629267, 20940051, 9259273, 24517008, 28220572) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 29, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: MAF -

Autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Hashimoto thyroiditis, susceptibility to

Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Apr 01, 2005

- -

TYPE 1 DIABETES MELLITUS 12, SUSCEPTIBILITY TO

Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Apr 01, 2005

- -

THYROID-ASSOCIATED ORBITOPATHY, SUSCEPTIBILITY TO

Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Apr 01, 2005

- -

Systemic lupus erythematosus, susceptibility to

Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Apr 01, 2005

- -

Celiac disease, susceptibility to, 3

Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Apr 01, 2005

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.057

BayesDel_addAF

Benign

-0.76

BayesDel_noAF

Benign

-0.72

CADD

Benign

0.46

DANN

Benign

0.46

DEOGEN2

Benign

0.24

T;T;.;.;.

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.042

LIST_S2

Benign

0.30

.;T;T;T;T

MetaRNN

Benign

0.000025

T;T;T;T;T

MetaSVM

Benign

-0.91

MutationAssessor

Benign

1.1

L;L;L;L;L

MutationTaster

Benign

1.0

P;P;P

PrimateAI

Benign

0.21

PROVEAN

Benign

0.28

.;N;N;.;N

REVEL

Benign

0.0070

Sift

Benign

0.18

.;T;T;.;T

Sift4G

Benign

0.21

.;T;T;.;T

Polyphen

0.0070

B;B;.;.;B

Vest4

0.047, 0.059, 0.027

MPC

0.66

ClinPred

0.012

GERP RS

-2.8

Varity_R

0.027

gMVP

0.33

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