11-68041801-C-T

Variant names:

• chr11-68041801-C-T
• rs36027301
• NM_006019.4:c.166C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001351059.2(TCIRG1):​c.-1084C>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 0.0527 in 1,609,634 control chromosomes in the GnomAD database, including 2,573 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.041 (174 hom., cov: 33)
  • Exomes 𝑓: 0.054 (2399 hom.)
• Consequence: TCIRG1 NM_001351059.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 1.32
• Publications: 28 publications found

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0089764595).
• BP6: Variant 11-68041801-C-T is Benign according to our data. Variant chr11-68041801-C-T is described in ClinVar as Benign. ClinVar VariationId is 305782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.057 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001351059.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCIRG1	NM_006019.4	MANE Select	c.166C>T	p.Arg56Trp	missense	Exon 3 of 20	NP_006010.2
	TCIRG1	NM_001351059.2		c.-1084C>T		5_prime_UTR_premature_start_codon_gain	Exon 3 of 19	NP_001337988.1
	TCIRG1	NM_001440552.1		c.166C>T	p.Arg56Trp	missense	Exon 4 of 21	NP_001427481.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCIRG1	ENST00000265686.8	TSL:1 MANE Select	c.166C>T	p.Arg56Trp	missense	Exon 3 of 20	ENSP00000265686.3	Q13488-1
	TCIRG1	ENST00000698255.1		c.166C>T	p.Arg56Trp	missense	Exon 3 of 20	ENSP00000513630.1	A0A8V8TM28
	TCIRG1	ENST00000698254.1		c.166C>T	p.Arg56Trp	missense	Exon 3 of 16	ENSP00000513629.1	A0A8V8TN16

Frequencies

GnomAD3 genomes AF: 0.0411 AC: 6256 AN: 152146 Hom.: 174 Cov.: 33

Gnomad AFR AF: 0.0106

Gnomad AMI AF: 0.0352

Gnomad AMR AF: 0.0336

Gnomad ASJ AF: 0.119

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.0174

Gnomad FIN AF: 0.0627

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.0585

Gnomad OTH AF: 0.0474

GnomAD2 exomes AF: 0.0462 AC: 11186 AN: 242334 AF XY: 0.0472

Gnomad AFR exome AF: 0.00717

Gnomad AMR exome AF: 0.0286

Gnomad ASJ exome AF: 0.117

Gnomad EAS exome AF: 0.000167

Gnomad FIN exome AF: 0.0678

Gnomad NFE exome AF: 0.0617

Gnomad OTH exome AF: 0.0528

GnomAD4 exome AF: 0.0539 AC: 78531 AN: 1457370 Hom.: 2399 Cov.: 32 AF XY: 0.0533 AC XY: 38637 AN XY: 724476

African (AFR) AF: 0.00766 AC: 256 AN: 33416

American (AMR) AF: 0.0300 AC: 1326 AN: 44224

Ashkenazi Jewish (ASJ) AF: 0.114 AC: 2975 AN: 26030

East Asian (EAS) AF: 0.0000506 AC: 2 AN: 39558

South Asian (SAS) AF: 0.0181 AC: 1544 AN: 85336

European-Finnish (FIN) AF: 0.0701 AC: 3703 AN: 52802

Middle Eastern (MID) AF: 0.0643 AC: 370 AN: 5750

European-Non Finnish (NFE) AF: 0.0586 AC: 65081 AN: 1110022

Other (OTH) AF: 0.0544 AC: 3274 AN: 60232

GnomAD4 genome AF: 0.0411 AC: 6254 AN: 152264 Hom.: 174 Cov.: 33 AF XY: 0.0404 AC XY: 3008 AN XY: 74440

African (AFR) AF: 0.0106 AC: 441 AN: 41570

American (AMR) AF: 0.0335 AC: 512 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.119 AC: 413 AN: 3470

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5170

South Asian (SAS) AF: 0.0178 AC: 86 AN: 4824

European-Finnish (FIN) AF: 0.0627 AC: 665 AN: 10610

Middle Eastern (MID) AF: 0.0782 AC: 23 AN: 294

European-Non Finnish (NFE) AF: 0.0585 AC: 3981 AN: 68004

Other (OTH) AF: 0.0469 AC: 99 AN: 2112

Alfa AF: 0.0548 Hom.: 953

Bravo AF: 0.0390

TwinsUK AF: 0.0553 AC: 205

ALSPAC AF: 0.0594 AC: 229

ESP6500AA AF: 0.0100 AC: 44

ESP6500EA AF: 0.0637 AC: 547

ExAC AF: 0.0448 AC: 5426

Asia WGS AF: 0.00924 AC: 34 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Autosomal recessive osteopetrosis 1 (3)
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	1	Disorder of bone (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Uncertain	-0.030
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.87	D
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.97	D
MetaRNN	Benign	0.0090	T
MetaSVM	Uncertain	0.062	D
MutationAssessor	Pathogenic	3.6	H
PhyloP100		1.3
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-5.4	D
REVEL	Pathogenic	0.67
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.23
MPC		0.67
ClinPred		0.11	T
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.68
gMVP		0.76
Mutation Taster		=86/14	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs36027301; hg19: chr11-67809268;