rs1840289391

Variant names:

• chr9-128907249-GACT-G
• rs1840289391
• NM_019594.4:c.88_90delTAC

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PM4_Supporting

The NM_019594.4(LRRC8A):​c.88_90delTAC​(p.Tyr30del) variant causes a conservative inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: LRRC8A NM_019594.4 conservative_inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.32
• Publications: 0 publications found

Genes affected

LRRC8A (HGNC:19027): (leucine rich repeat containing 8 VRAC subunit A) This gene encodes a protein belonging to the leucine-rich repeat family of proteins, which are involved in diverse biological processes, including cell adhesion, cellular trafficking, and hormone-receptor interactions. This family member is a putative four-pass transmembrane protein that plays a role in B cell development. Defects in this gene cause autosomal dominant non-Bruton type agammaglobulinemia, an immunodeficiency disease resulting from defects in B cell maturation. Multiple alternatively spliced transcript variants, which encode the same protein, have been identified for this gene. [provided by RefSeq, Jul 2008]

LRRC8A Gene-Disease associations (from GenCC):

• autosomal agammaglobulinemia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• agammaglobulinemia

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• agammaglobulinemia 5, autosomal dominant

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_019594.4. Strenght limited to Supporting due to length of the change: 1aa.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_019594.4. 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
	LRRC8A	NM_019594.4	MANE Select	c.88_90delTAC	p.Tyr30del	conservative_inframe_deletion	Exon 3 of 4	NP_062540.2	Q8IWT6
	LRRC8A	NM_001127244.2		c.88_90delTAC	p.Tyr30del	conservative_inframe_deletion	Exon 3 of 4	NP_001120716.1	Q8IWT6
	LRRC8A	NM_001127245.2		c.88_90delTAC	p.Tyr30del	conservative_inframe_deletion	Exon 2 of 3	NP_001120717.1	Q8IWT6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRRC8A	ENST00000372600.9	TSL:1 MANE Select	c.88_90delTAC	p.Tyr30del	conservative_inframe_deletion	Exon 3 of 4	ENSP00000361682.4	Q8IWT6
	LRRC8A	ENST00000372599.7	TSL:1	c.88_90delTAC	p.Tyr30del	conservative_inframe_deletion	Exon 2 of 3	ENSP00000361680.3	Q8IWT6
	LRRC8A	ENST00000927475.1		c.88_90delTAC	p.Tyr30del	conservative_inframe_deletion	Exon 3 of 5	ENSP00000597534.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs1840289391; hg19: chr9-131669528;