rs34227834

Positions:

• chr11-68043010-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_006019.4(TCIRG1):​c.482C>T​(p.Pro161Leu) variant causes a missense 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P161P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0026 (7 hom.)
• Consequence: TCIRG1 NM_006019.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: -0.145

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 235740.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=3}. Variant chr11-68043010-C-T is described in Lovd as [Likely_benign].
• 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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TCIRG1	NM_006019.4	c.482C>T	p.Pro161Leu	missense_variant	5/20	ENST00000265686.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TCIRG1	ENST00000265686.8	c.482C>T	p.Pro161Leu	missense_variant	5/20	1	NM_006019.4	P1

Frequencies

GnomAD3 genomes AF: 0.00140 AC: 213 AN: 152114 Hom.: 0 Cov.: 33

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

GnomAD3 exomes AF: 0.00142 AC: 221 AN: 155316 Hom.: 0 AF XY: 0.00130 AC XY: 108 AN XY: 82844

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 SAS 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.: 7 Cov.: 35 AF XY: 0.00249 AC XY: 1718 AN XY: 690538

Gnomad4 AFR exome AF: 0.000253

Gnomad4 AMR exome AF: 0.00216

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000558

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000831

Gnomad4 NFE exome AF: 0.00313

Gnomad4 OTH exome AF: 0.00210

GnomAD4 genome AF: 0.00140 AC: 213 AN: 152232 Hom.: 0 Cov.: 33 AF XY: 0.00128 AC XY: 95 AN XY: 74434

Gnomad4 AFR AF: 0.000529

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.00247

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00197 Hom.: 0

Bravo AF: 0.00161

TwinsUK AF: 0.00324 AC: 12

ALSPAC AF: 0.00415 AC: 16

ESP6500AA AF: 0.000474 AC: 2

ESP6500EA AF: 0.00108 AC: 9

ExAC AF: 0.000432 AC: 44

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:4

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 08, 2019	Reported (as rs34227834) in association reduced neutrophil count (Rosenthal et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27229898) -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 15, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Autosomal recessive osteopetrosis 1 Benign:2

Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	18
DANN	Benign	0.65
DEOGEN2	Benign	0.29	T;T;T
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.68	T;T;T
M_CAP	Benign	0.084	D
MetaRNN	Benign	0.0071	T;T;T
MetaSVM	Benign	-0.47	T
MutationAssessor	Benign	1.8	L;.;.
MutationTaster	Benign	0.97	D;N
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.75	N;N;N
REVEL	Benign	0.19
Sift	Benign	0.15	T;T;T
Sift4G	Benign	0.36	T;T;T
Polyphen		0.50	P;.;.
Vest4		0.10
MVP		0.80
MPC		0.16
ClinPred		0.018	T
GERP RS		3.5
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.0
Varity_R		0.049
gMVP		0.41

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

Other links and lift over

dbSNP: rs34227834; hg19: chr11-67810477; COSMIC: COSV55837609; COSMIC: COSV55837609;