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rs231775

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. 13/19 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

13

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3O: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]

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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 UniProt
CTLA4NM_005214.5 linkuse as main transcriptc.49A>G p.Thr17Ala missense_variant 1/4 ENST00000648405.2
CTLA4NM_001037631.3 linkuse as main transcriptc.49A>G p.Thr17Ala missense_variant 1/3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CTLA4ENST00000648405.2 linkuse as main transcriptc.49A>G p.Thr17Ala missense_variant 1/4 NM_005214.5 P1P16410-1

Frequencies

GnomAD3 genomes
AF:
0.400
AC:
60714
AN:
151936
Hom.:
12575
Cov.:
32
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.:
39
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.:
32
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:3Other:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:1Other:1
Benign, criteria provided, single submitterclinical testingGeneDxNov 10, 2018This 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 provided, no classification providedphenotyping onlyGenomeConnect, 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 submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineMar 29, 2016Variant 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 haploinsuffiency Benign:1
Benign, criteria provided, single submitterclinical testingInvitaeFeb 01, 2024- -
TYPE 1 DIABETES MELLITUS 12, SUSCEPTIBILITY TO Other:1
risk factor, no assertion criteria providedliterature onlyOMIMApr 01, 2005- -
Hashimoto thyroiditis, susceptibility to Other:1
risk factor, no assertion criteria providedliterature onlyOMIMApr 01, 2005- -
Systemic lupus erythematosus, susceptibility to Other:1
risk factor, no assertion criteria providedliterature onlyOMIMApr 01, 2005- -
Thyroid-associated orbitopathy, susceptibility to Other:1
risk factor, no assertion criteria providedliterature onlyOMIMApr 01, 2005- -
Celiac disease, susceptibility to, 3 Other:1
risk factor, no assertion criteria providedliterature onlyOMIMApr 01, 2005- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.057
BayesDel_addAF
Benign
-0.76
T
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
N
MetaRNN
Benign
0.000025
T;T;T;T;T
MetaSVM
Benign
-0.91
T
MutationAssessor
Benign
1.1
L;L;L;L;L
MutationTaster
Benign
1.0
P;P;P
PrimateAI
Benign
0.21
T
Polyphen
0.0070
B;B;.;.;B
Vest4
0.047, 0.059, 0.027
MPC
0.66
ClinPred
0.012
T
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.

Other links and lift over

dbSNP: rs231775; hg19: chr2-204732714; COSMIC: COSV55592023; COSMIC: COSV55592023; API