11-68041392-A-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PS3PP3PP5_Very_Strong

The NM_006019.4(TCIRG1):c.117+4A>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000349 in 1,603,244 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV005086094: Minigene assay and RT-PCR show this variant results in the activation of an upstream cryptic splice site, causing an in-frame deletion of 14 amino acids in exon 2 and also exon 2 skipping (PMID:15300850, 10942435, 24989235)." and additional evidence is available in ClinVar.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000037 ( 0 hom. )

Consequence

TCIRG1
NM_006019.4 splice_region, intron

Scores

Splicing: ADA: 0.9991

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12

Conservation

PhyloP100: 1.98

Publications

5 publications found

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]

TCIRG1 Gene-Disease associations (from GenCC):

autosomal recessive osteopetrosis
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Myriad Women’s Health, Orphanet
autosomal recessive osteopetrosis 1
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, ClinGen, Labcorp Genetics (formerly Invitae), PanelApp Australia
autosomal dominant severe congenital neutropenia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
autosomal recessive osteopetrosis 6
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
dysosteosclerosis
Inheritance: AR Classification: SUPPORTIVE, LIMITED Submitted by: ClinGen, Orphanet

TCIRG1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 13 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV005086094: Minigene assay and RT-PCR show this variant results in the activation of an upstream cryptic splice site, causing an in-frame deletion of 14 amino acids in exon 2 and also exon 2 skipping (PMID: 15300850, 10942435, 24989235).; SCV000962844: Studies have shown that this variant results in the activation of a cryptic splice site in 2 (PMID: 10942435, 24989235).; SCV001753451: Functional studies indicate that this splice site variant results int the activation of an upstream cryptic splice donor site and causes an in-frame deletion of exon 2 (Susani et al., 2004);; SCV003707028: Functional studies using RT-PCR analysis demonstrated that this alteration affected splicing, resulting in a 14 amino acid deletion located in the N-terminal, intracellular portion of the protein (Kornak, 2000).; SCV004847403: in vitro functional studies using patient fibroblasts and minigene assays have shown that this variant activates an upstream cryptic splice site (also predicted by computational tools) which results in the deletion of 42 nucleotides from the transcript, resulting in the loss of 14 amino acid residues but preserving the integrity of the protein reading-frame (Kornak 2000 PMID: 10942435, Susani 2004 PMID: 15300850).; SCV005362904: a functional study suggested that this variant causes splicing defects (Susani et al. 2004. PubMed ID: 15300850).

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 11-68041392-A-T is Pathogenic according to our data. Variant chr11-68041392-A-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 5462.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006019.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
TCIRG1	NM_006019.4	MANE Select	c.117+4A>T	splice_region intron	N/A	NP_006010.2
TCIRG1	NM_001440552.1		c.117+4A>T	splice_region intron	N/A	NP_001427481.1
TCIRG1	NM_001440553.1		c.117+4A>T	splice_region intron	N/A	NP_001427482.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TCIRG1	ENST00000265686.8	TSL:1 MANE Select	c.117+4A>T	splice_region intron	N/A	ENSP00000265686.3	Q13488-1
TCIRG1	ENST00000698255.1		c.117+4A>T	splice_region intron	N/A	ENSP00000513630.1	A0A8V8TM28
TCIRG1	ENST00000698254.1		c.117+4A>T	splice_region intron	N/A	ENSP00000513629.1	A0A8V8TN16

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152030

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000577

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000443

AC:

AN:

248134

AF XY:

0.0000520

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000903

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000179

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000365

AC:

AN:

1451214

Hom.:

Cov.:

AF XY:

0.0000402

AC XY:

AN XY:

721898

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33288

American (AMR)

AF:

0.00

AC:

AN:

44676

Ashkenazi Jewish (ASJ)

AF:

0.00134

AC:

AN:

26064

East Asian (EAS)

AF:

0.00

AC:

AN:

39572

South Asian (SAS)

AF:

0.00

AC:

AN:

86082

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52082

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5660

European-Non Finnish (NFE)

AF:

0.00000997

AC:

AN:

1103768

Other (OTH)

AF:

0.000117

AC:

AN:

60022

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.529

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000197

AC:

AN:

152030

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74266

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41366

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.000577

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67984

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.0000522

Hom.:

Bravo

AF:

0.0000453

EpiCase

AF:

0.000164

EpiControl

AF:

0.00

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Autosomal recessive osteopetrosis 1 (7)

not provided (2)

Autosomal recessive osteopetrosis (1)

Inborn genetic diseases (1)

TCIRG1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.27

CADD

Benign

(source)

DANN

Benign

0.97

PhyloP100

2.0

Mutation Taster

=12/88

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.94

Splicevardb

3.0

SpliceAI score (max)

0.66

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.66

Position offset: -46

DS_DL_spliceai

0.50

Position offset: -4

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over