rs140963213

Variant names:

• chr11-68047516-G-A
• rs140963213
• NM_006019.4:c.1249G>A

Your query was ambiguous. Multiple possible variants found:

• chr11-68047516-G-A
• chr11-68047516-G-T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 3P and 7B. PM1 PP3 BP4_Moderate BS1_Supporting BS2

The NM_006019.4(TCIRG1):​c.1249G>A​(p.Ala417Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00378 in 1,613,942 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0026 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0039 (12 hom.)
• Consequence: TCIRG1 NM_006019.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10 B:3 O:1
• Conservation: PhyloP100: 6.59
• Publications: 19 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: Likely_benign. The variant received -4 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_006019.4
• PP3: Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, BayesDel_noAF, Cadd, Dann, M_CAP, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.09511113).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00264 (401/152182) while in subpopulation NFE AF = 0.00403 (274/67996). AF 95% confidence interval is 0.00364. There are 2 homozygotes in GnomAd4. There are 164 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 2 AR,AD gene

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.1249G>A	p.Ala417Thr	missense	Exon 11 of 20	NP_006010.2
	TCIRG1	NM_001440552.1		c.1249G>A	p.Ala417Thr	missense	Exon 12 of 21	NP_001427481.1
	TCIRG1	NM_001440553.1		c.1249G>A	p.Ala417Thr	missense	Exon 11 of 20	NP_001427482.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCIRG1	ENST00000265686.8	TSL:1 MANE Select	c.1249G>A	p.Ala417Thr	missense	Exon 11 of 20	ENSP00000265686.3	Q13488-1
	TCIRG1	ENST00000532635.5	TSL:1	c.601G>A	p.Ala201Thr	missense	Exon 6 of 15	ENSP00000434407.1	Q13488-2
	TCIRG1	ENST00000698255.1		c.1198G>A	p.Ala400Thr	missense	Exon 11 of 20	ENSP00000513630.1	A0A8V8TM28

Frequencies

GnomAD3 genomes AF: 0.00264 AC: 402 AN: 152064 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00130

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00268

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00142

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00403

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00254 AC: 637 AN: 250824 AF XY: 0.00258

Gnomad AFR exome AF: 0.000989

Gnomad AMR exome AF: 0.00234

Gnomad ASJ exome AF: 0.00249

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000786

Gnomad NFE exome AF: 0.00424

Gnomad OTH exome AF: 0.00180

GnomAD4 exome AF: 0.00390 AC: 5705 AN: 1461760 Hom.: 12 Cov.: 36 AF XY: 0.00381 AC XY: 2774 AN XY: 727190

African (AFR) AF: 0.000747 AC: 25 AN: 33478

American (AMR) AF: 0.00219 AC: 98 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00268 AC: 70 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.000104 AC: 9 AN: 86258

European-Finnish (FIN) AF: 0.00103 AC: 55 AN: 53322

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00474 AC: 5275 AN: 1111994

Other (OTH) AF: 0.00283 AC: 171 AN: 60392

GnomAD4 genome AF: 0.00264 AC: 401 AN: 152182 Hom.: 2 Cov.: 33 AF XY: 0.00220 AC XY: 164 AN XY: 74390

African (AFR) AF: 0.00130 AC: 54 AN: 41506

American (AMR) AF: 0.00261 AC: 40 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00403 AC: 14 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00142 AC: 15 AN: 10586

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00403 AC: 274 AN: 67996

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.00362 Hom.: 4

Bravo AF: 0.00274

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00467 AC: 18

ESP6500AA AF: 0.00114 AC: 5

ESP6500EA AF: 0.00489 AC: 42

ExAC AF: 0.00246 AC: 298

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00338

EpiControl AF: 0.00462

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	4	2	not provided (6)
-	3	1	Autosomal recessive osteopetrosis 1 (5)
-	1	-	Disorder of bone (1)
-	1	-	Neutropenia, severe congenital, 1, autosomal dominant (1)
-	1	-	TCIRG1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.82	D
Eigen	Uncertain	0.35
Eigen_PC	Benign	0.22
FATHMM_MKL	Benign	0.35	N
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.40	D
MetaRNN	Benign	0.095	T
MetaSVM	Uncertain	0.75	D
PhyloP100		6.6
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-3.6	D
REVEL	Pathogenic	0.75
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.91
MVP		0.94
MPC		0.52
ClinPred		0.030	T
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.53
gMVP		0.93
Mutation Taster		=56/44	polymorphism

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: rs140963213; hg19: chr11-67814983; COSMIC: COSV105048244; COSMIC: COSV105048244;