11-68049469-A-G

Variant names:

• chr11-68049469-A-G
• rs2075609
• NM_006019.4:c.1887+175A>G

Variant summary

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

The NM_006019.4(TCIRG1):​c.1887+175A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.277 in 980,062 control chromosomes in the GnomAD database, including 39,353 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.31 (8005 hom., cov: 33)
  • Exomes 𝑓: 0.27 (31348 hom.)
• Consequence: TCIRG1 NM_006019.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.375
• Publications: 22 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 (BayesDel_noAF=-0.89).
• BP6: Variant 11-68049469-A-G is Benign according to our data. Variant chr11-68049469-A-G is described in ClinVar as Benign. ClinVar VariationId is 1276806.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.435 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCIRG1	NM_006019.4	MANE Select	c.1887+175A>G		intron	N/A	NP_006010.2
	TCIRG1	NM_001440552.1		c.1887+175A>G		intron	N/A	NP_001427481.1
	TCIRG1	NM_001440553.1		c.1887+175A>G		intron	N/A	NP_001427482.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCIRG1	ENST00000265686.8	TSL:1 MANE Select	c.1887+175A>G		intron	N/A	ENSP00000265686.3	Q13488-1
	TCIRG1	ENST00000532635.5	TSL:1	c.1239+175A>G		intron	N/A	ENSP00000434407.1	Q13488-2
	TCIRG1	ENST00000524870.1	TSL:1	n.322A>G		non_coding_transcript_exon	Exon 1 of 3

Frequencies

GnomAD3 genomes AF: 0.314 AC: 47804 AN: 152022 Hom.: 7992 Cov.: 33

Gnomad AFR AF: 0.440

Gnomad AMI AF: 0.339

Gnomad AMR AF: 0.241

Gnomad ASJ AF: 0.245

Gnomad EAS AF: 0.311

Gnomad SAS AF: 0.250

Gnomad FIN AF: 0.204

Gnomad MID AF: 0.231

Gnomad NFE AF: 0.281

Gnomad OTH AF: 0.293

GnomAD4 exome AF: 0.270 AC: 223331 AN: 827922 Hom.: 31348 Cov.: 11 AF XY: 0.269 AC XY: 112643 AN XY: 418710

African (AFR) AF: 0.441 AC: 8825 AN: 20010

American (AMR) AF: 0.194 AC: 5012 AN: 25892

Ashkenazi Jewish (ASJ) AF: 0.258 AC: 4454 AN: 17244

East Asian (EAS) AF: 0.305 AC: 10023 AN: 32818

South Asian (SAS) AF: 0.245 AC: 14441 AN: 58908

European-Finnish (FIN) AF: 0.218 AC: 6653 AN: 30460

Middle Eastern (MID) AF: 0.269 AC: 757 AN: 2812

European-Non Finnish (NFE) AF: 0.270 AC: 162510 AN: 601078

Other (OTH) AF: 0.275 AC: 10656 AN: 38700

GnomAD4 genome AF: 0.315 AC: 47859 AN: 152140 Hom.: 8005 Cov.: 33 AF XY: 0.309 AC XY: 23002 AN XY: 74370

African (AFR) AF: 0.441 AC: 18269 AN: 41466

American (AMR) AF: 0.241 AC: 3681 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.245 AC: 852 AN: 3472

East Asian (EAS) AF: 0.311 AC: 1606 AN: 5162

South Asian (SAS) AF: 0.249 AC: 1206 AN: 4834

European-Finnish (FIN) AF: 0.204 AC: 2167 AN: 10612

Middle Eastern (MID) AF: 0.231 AC: 68 AN: 294

European-Non Finnish (NFE) AF: 0.281 AC: 19087 AN: 67978

Other (OTH) AF: 0.291 AC: 616 AN: 2114

Alfa AF: 0.271 Hom.: 6533

Bravo AF: 0.320

Asia WGS AF: 0.303 AC: 1055 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Autosomal recessive osteopetrosis 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.68
DANN	Benign	0.50
PhyloP100		-0.38
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2075609; hg19: chr11-67816936;