11-68050524-AGGCCTG-AGGCCTGGGCCTG

Variant names:

• chr11-68050524-A-AGGCCTG
• rs199973759
• NM_006019.4:c.2285_2290dupTGGGCC

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP3 BP6_Very_Strong BA1

The NM_006019.4(TCIRG1):​c.2285_2290dupTGGGCC​(p.Leu762_Gly763dup) variant causes a disruptive inframe insertion change. The variant allele was found at a frequency of 0.00361 in 1,613,774 control chromosomes in the GnomAD database, including 196 homozygotes. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. R764R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.019 (101 hom., cov: 33)
  • Exomes 𝑓: 0.0020 (95 hom.)
• Consequence: TCIRG1 NM_006019.4 disruptive_inframe_insertion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 5.46
• Publications: 0 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)
• 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

ENSG00000255031 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_006019.4
• BP6: Variant 11-68050524-A-AGGCCTG is Benign according to our data. Variant chr11-68050524-A-AGGCCTG is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 305820.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0649 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCIRG1	NM_006019.4	MANE Select	c.2285_2290dupTGGGCC	p.Leu762_Gly763dup	disruptive_inframe_insertion	Exon 19 of 20	NP_006010.2
	TCIRG1	NM_001440552.1		c.2285_2290dupTGGGCC	p.Leu762_Gly763dup	disruptive_inframe_insertion	Exon 20 of 21	NP_001427481.1
	TCIRG1	NM_001440553.1		c.2285_2290dupTGGGCC	p.Leu762_Gly763dup	disruptive_inframe_insertion	Exon 19 of 20	NP_001427482.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCIRG1	ENST00000265686.8	TSL:1 MANE Select	c.2285_2290dupTGGGCC	p.Leu762_Gly763dup	disruptive_inframe_insertion	Exon 19 of 20	ENSP00000265686.3
	TCIRG1	ENST00000532635.5	TSL:1	c.1637_1642dupTGGGCC	p.Leu546_Gly547dup	disruptive_inframe_insertion	Exon 14 of 15	ENSP00000434407.1
	TCIRG1	ENST00000530449.2	TSL:1	n.1510_1515dupTGGGCC		non_coding_transcript_exon	Exon 6 of 6

Frequencies

GnomAD3 genomes AF: 0.0194 AC: 2954 AN: 152188 Hom.: 101 Cov.: 33

Gnomad AFR AF: 0.0671

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00765

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.0186

GnomAD2 exomes AF: 0.00509 AC: 1278 AN: 251248 AF XY: 0.00391

Gnomad AFR exome AF: 0.0688

Gnomad AMR exome AF: 0.00333

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000185

Gnomad OTH exome AF: 0.00326

GnomAD4 exome AF: 0.00196 AC: 2864 AN: 1461468 Hom.: 95 Cov.: 33 AF XY: 0.00168 AC XY: 1222 AN XY: 727064

African (AFR) AF: 0.0681 AC: 2281 AN: 33476

American (AMR) AF: 0.00369 AC: 165 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000197 AC: 17 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53138

Middle Eastern (MID) AF: 0.00105 AC: 6 AN: 5688

European-Non Finnish (NFE) AF: 0.000111 AC: 123 AN: 1111982

Other (OTH) AF: 0.00450 AC: 272 AN: 60378

GnomAD4 genome AF: 0.0194 AC: 2956 AN: 152306 Hom.: 101 Cov.: 33 AF XY: 0.0183 AC XY: 1364 AN XY: 74468

African (AFR) AF: 0.0670 AC: 2783 AN: 41554

American (AMR) AF: 0.00764 AC: 117 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000221 AC: 15 AN: 68022

Other (OTH) AF: 0.0184 AC: 39 AN: 2116

Alfa AF: 0.00114 Hom.: 0

Bravo AF: 0.0217

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000178

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Osteopetrosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.5
Mutation Taster		=67/33	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs199973759; hg19: chr11-67817991; COSMIC: COSV55835572; COSMIC: COSV55835572;