rs231775

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -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. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T17I) has been classified as Uncertain significance.

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 was made for transcript

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
CTLA4	NM_005214.5 link	c.49A>G	p.Thr17Ala	missense_variant	Exon 1 of 4	ENST00000648405.2	NP_005205.2	P16410-1
CTLA4	NM_001037631.3 link	c.49A>G	p.Thr17Ala	missense_variant	Exon 1 of 3		NP_001032720.1	P16410-5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTLA4	ENST00000648405.2 link	c.49A>G	p.Thr17Ala	missense_variant	Exon 1 of 4		NM_005214.5	ENSP00000497102.1		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

GnomAD2 exomes

AF:

0.415

AC:

104287

AN:

251236

AF XY:

0.406

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 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

AC:

12658

AN:

33466

Gnomad4 AMR exome

AF:

0.454

AC:

20277

AN:

44692

Gnomad4 ASJ exome

AF:

0.302

AC:

7881

AN:

26128

Gnomad4 EAS exome

AF:

0.645

AC:

25599

AN:

39686

Gnomad4 SAS exome

AF:

0.321

AC:

27644

AN:

86198

Gnomad4 FIN exome

AF:

0.529

AC:

28251

AN:

53398

Gnomad4 NFE exome

AF:

0.384

AC:

426516

AN:

1111320

Gnomad4 Remaining exome

AF:

0.391

AC:

23632

AN:

60372

Heterozygous variant carriers

16482

32964

49447

65929

82411

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

13460

26920

40380

53840

67300

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

AC:

0.374277

AN:

0.374277

Gnomad4 AMR

AF:

0.412

AC:

0.412449

AN:

0.412449

Gnomad4 ASJ

AF:

0.300

AC:

0.300173

AN:

0.300173

Gnomad4 EAS

AF:

0.644

AC:

0.644354

AN:

0.644354

Gnomad4 SAS

AF:

0.321

AC:

0.321488

AN:

0.321488

Gnomad4 FIN

AF:

0.530

AC:

0.529695

AN:

0.529695

Gnomad4 NFE

AF:

0.386

AC:

0.38558

AN:

0.38558

Gnomad4 OTH

AF:

0.358

AC:

0.358294

AN:

0.358294

Heterozygous variant carriers

1866

3732

5599

7465

9331

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Genome Hom

Variant carriers

572

1144

1716

2288

2860

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.382

Hom.:

48510

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

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

GenomeConnect, ClinGen

Significance:not provided

Review Status:no classification provided

Collection Method:phenotyping only

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. -

Nov 10, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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) -

not specified

Benign:1

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

TYPE 1 DIABETES MELLITUS 12, SUSCEPTIBILITY TO

Other:1

Apr 01, 2005

OMIM

Significance:risk factor

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Hashimoto thyroiditis, susceptibility to

Other:1

Apr 01, 2005

OMIM

Significance:risk factor

Review Status:no assertion criteria provided

Collection Method:literature only

- -

THYROID-ASSOCIATED ORBITOPATHY, SUSCEPTIBILITY TO

Other:1

Apr 01, 2005

OMIM

Significance:risk factor

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Systemic lupus erythematosus, susceptibility to

Other:1

Apr 01, 2005

OMIM

Significance:risk factor

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Celiac disease, susceptibility to, 3

Other:1

Apr 01, 2005

OMIM

Significance:risk factor

Review Status:no assertion criteria provided

Collection Method:literature only

- -

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

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

Mutation Taster

=99/1

polymorphism (auto)

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