NM_006019.4:c.630+2T>C

Variant names:

• chr11-68043499-T-C
• rs1392364437
• NM_006019.4:c.630+2T>C

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_006019.4(TCIRG1):​c.630+2T>C variant causes a splice donor, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TCIRG1 NM_006019.4 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 4.45
• Publications: 1 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: Pathogenic. The variant received 18 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-68043499-T-C is Pathogenic according to our data. Variant chr11-68043499-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 551426.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.630+2T>C		splice_donor intron	N/A	NP_006010.2
	TCIRG1	NM_001440552.1		c.630+2T>C		splice_donor intron	N/A	NP_001427481.1
	TCIRG1	NM_001440553.1		c.630+2T>C		splice_donor 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.630+2T>C		splice_donor intron	N/A	ENSP00000265686.3	Q13488-1
	TCIRG1	ENST00000532635.5	TSL:1	c.-19+2T>C		splice_donor intron	N/A	ENSP00000434407.1	Q13488-2
	TCIRG1	ENST00000698255.1		c.630+2T>C		splice_donor intron	N/A	ENSP00000513630.1	A0A8V8TM28

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00 AC: 0 AN: 180174 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1421026 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 703436

African (AFR) AF: 0.00 AC: 0 AN: 32630

American (AMR) AF: 0.00 AC: 0 AN: 38694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25366

East Asian (EAS) AF: 0.00 AC: 0 AN: 37602

South Asian (SAS) AF: 0.00 AC: 0 AN: 81404

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49074

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5690

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1091698

Other (OTH) AF: 0.00 AC: 0 AN: 58868

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Autosomal recessive osteopetrosis 1 (4)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Benign	-0.18
CADD	Pathogenic	30
DANN	Benign	0.88
Eigen	Pathogenic	0.74
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.94	D
PhyloP100		4.4
GERP RS		0.61
PromoterAI		-0.053	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Mutation Taster		=4/96	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.25		Position offset: -41
DS_DL_spliceai		0.98		Position offset: -2

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

Other links and lift over

dbSNP: rs1392364437; hg19: chr11-67810966;