Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The ENST00000532635.5(TCIRG1):c.-506C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00245 in 1,551,700 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0014 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0026 ( 7 hom. )

Consequence

TCIRG1
ENST00000532635.5 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:6

Conservation

PhyloP100: -0.145

Publications

10 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)
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: Orphanet, ClinGen

TCIRG1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0070929825).

BP6

Variant 11-68043010-C-T is Benign according to our data. Variant chr11-68043010-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 235740.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0014 (213/152232) while in subpopulation NFE AF = 0.00247 (168/67964). AF 95% confidence interval is 0.00217. There are 0 homozygotes in GnomAd4. There are 95 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 7 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000532635.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TCIRG1	NM_006019.4	MANE Select	c.482C>T	p.Pro161Leu	missense	Exon 5 of 20	NP_006010.2
TCIRG1	NM_006053.4		c.-506C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 15	NP_006044.1
TCIRG1	NM_001351059.2		c.-768C>T		5_prime_UTR_premature_start_codon_gain	Exon 5 of 19	NP_001337988.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TCIRG1	ENST00000532635.5	TSL:1	c.-506C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 15	ENSP00000434407.1
TCIRG1	ENST00000265686.8	TSL:1 MANE Select	c.482C>T	p.Pro161Leu	missense	Exon 5 of 20	ENSP00000265686.3
TCIRG1	ENST00000532635.5	TSL:1	c.-506C>T		5_prime_UTR	Exon 1 of 15	ENSP00000434407.1

Frequencies

GnomAD3 genomes

AF:

0.00140

AC:

213

AN:

152114

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000531

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00118

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00247

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.00142

AC:

221

AN:

155316

AF XY:

0.00130

show subpopulations

Gnomad AFR exome

AF:

0.000364

Gnomad AMR exome

AF:

0.00211

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000649

Gnomad NFE exome

AF:

0.00263

Gnomad OTH exome

AF:

0.00182

GnomAD4 exome

AF:

0.00257

AC:

3596

AN:

1399468

Hom.:

Cov.:

AF XY:

0.00249

AC XY:

1718

AN XY:

690538

show subpopulations

African (AFR)

AF:

0.000253

AC:

AN:

31640

American (AMR)

AF:

0.00216

AC:

AN:

36146

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25188

East Asian (EAS)

AF:

0.0000558

AC:

AN:

35842

South Asian (SAS)

AF:

0.00

AC:

AN:

79388

European-Finnish (FIN)

AF:

0.0000831

AC:

AN:

48140

Middle Eastern (MID)

AF:

0.000370

AC:

AN:

5410

European-Non Finnish (NFE)

AF:

0.00313

AC:

3380

AN:

1079738

Other (OTH)

AF:

0.00210

AC:

122

AN:

57976

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

211

422

634

845

1056

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

138

276

414

552

690

<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:

0.00140

AC:

213

AN:

152232

Hom.:

Cov.:

AF XY:

0.00128

AC XY:

AN XY:

74434

show subpopulations

African (AFR)

AF:

0.000529

AC:

AN:

41560

American (AMR)

AF:

0.00118

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5162

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0000941

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00247

AC:

168

AN:

67964

Other (OTH)

AF:

0.00142

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

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:

0.00190

Hom.:

Bravo

AF:

0.00161

TwinsUK

AF:

0.00324

AC:

ALSPAC

AF:

0.00415

AC:

ESP6500AA

AF:

0.000474

AC:

ESP6500EA

AF:

0.00108

AC:

ExAC

AF:

0.000432

AC:

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

Autosomal recessive osteopetrosis 1 (3)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.29

CADD

Benign

(source)

DANN

Benign

0.65

DEOGEN2

Benign

0.29

Eigen

Benign

-0.51

Eigen_PC

Benign

-0.56

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.68

M_CAP

Benign

0.084

MetaRNN

Benign

0.0071

MetaSVM

Benign

-0.47

MutationAssessor

Benign

1.8

PhyloP100

-0.14

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-0.75

REVEL

Benign

0.19

Sift

Benign

0.15

Sift4G

Benign

0.36

Polyphen

0.50

Vest4

0.10

MVP

0.80

MPC

0.16

ClinPred

0.018

GERP RS

3.5

PromoterAI

-0.066

Neutral

(source)

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.0

Varity_R

0.049

gMVP

0.41

Mutation Taster

=298/2

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

rs34227834

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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over