11-68043654-G-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PM2

The NM_006019.4(TCIRG1):​c.713+1G>A variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.000000688 in 1,454,366 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 34)
Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

TCIRG1
NM_006019.4 splice_donor, intron

Scores

5
1
1
Splicing: ADA: 1.000
2

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.51
Variant links:
Genes affected
TCIRG1 (HGNC:11647): (T cell immune regulator 1, ATPase H+ transporting V0 subunit a3) This gene encodes a subunit of a large protein complex known as a vacuolar H+-ATPase (V-ATPase). The protein complex acts as a pump to move protons across the membrane. This movement of protons helps regulate the pH of cells and their surrounding environment. V-ATPase dependent organelle acidification is necessary for such intracellular processes as protein sorting, zymogen activation, and receptor-mediated endocytosis. V-ATPase is comprised of a cytosolic V1 domain and a transmembrane V0 domain. Alternative splicing results in multiple transcript variants. Mutations in this gene are associated with infantile malignant osteopetrosis. [provided by RefSeq, May 2017]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PVS1
Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 6, offset of -40, new splice context is: gggGTgagc. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
TCIRG1NM_006019.4 linkc.713+1G>A splice_donor_variant, intron_variant ENST00000265686.8 NP_006010.2 Q13488-1A0A024R5E5

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
TCIRG1ENST00000265686.8 linkc.713+1G>A splice_donor_variant, intron_variant 1 NM_006019.4 ENSP00000265686.3 Q13488-1

Frequencies

GnomAD3 genomes
Cov.:
34
GnomAD4 exome
AF:
6.88e-7
AC:
1
AN:
1454366
Hom.:
0
Cov.:
34
AF XY:
0.00
AC XY:
0
AN XY:
722808
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000117
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
34
Alfa
AF:
0.0000457
Hom.:
0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.63
D
BayesDel_noAF
Pathogenic
0.21
CADD
Pathogenic
34
DANN
Uncertain
0.99
Eigen
Pathogenic
1.1
Eigen_PC
Pathogenic
0.89
FATHMM_MKL
Pathogenic
0.98
D
GERP RS
4.6

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.93
SpliceAI score (max)
1.0
Details are displayed if max score is > 0.2
DS_DG_spliceai
0.45
Position offset: -41
DS_DL_spliceai
1.0
Position offset: -1

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: rs774308815; hg19: chr11-67811121; API