Genetic Variant NM_019594.4:c.44C>T (chr9-128907208-C-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_019594.4(LRRC8A):c.44C>T(p.Pro15Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

LRRC8A
NM_019594.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.91

Publications

6 publications found

Variant links:

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)

LRRC8A links:

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ACMG classification

Classification was made for transcript

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

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.811

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LRRC8A	NM_019594.4	MANE Select	c.44C>T	p.Pro15Leu	missense	Exon 3 of 4	NP_062540.2	Q8IWT6
LRRC8A	NM_001127244.2		c.44C>T	p.Pro15Leu	missense	Exon 3 of 4	NP_001120716.1	Q8IWT6
LRRC8A	NM_001127245.2		c.44C>T	p.Pro15Leu	missense	Exon 2 of 3	NP_001120717.1	Q8IWT6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LRRC8A	ENST00000372600.9	TSL:1 MANE Select	c.44C>T	p.Pro15Leu	missense	Exon 3 of 4	ENSP00000361682.4	Q8IWT6
LRRC8A	ENST00000372599.7	TSL:1	c.44C>T	p.Pro15Leu	missense	Exon 2 of 3	ENSP00000361680.3	Q8IWT6
LRRC8A	ENST00000927475.1		c.44C>T	p.Pro15Leu	missense	Exon 3 of 5	ENSP00000597534.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

251172

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:

AN:

1460738

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726410

African (AFR)

AF:

0.00

AC:

AN:

33456

American (AMR)

AF:

0.00

AC:

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39666

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53264

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111150

Other (OTH)

AF:

0.00

AC:

AN:

60348

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.55

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Uncertain

0.10

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.22

Eigen

Uncertain

0.62

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

M_CAP

Benign

0.046

MetaRNN

Pathogenic

0.81

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

PhyloP100

7.9

PrimateAI

Pathogenic

0.93

PROVEAN

Uncertain

-3.5

REVEL

Uncertain

0.42

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0040

Polyphen

0.97

Vest4

0.84

MutPred

0.51

Gain of stability (P = 0.0061)

MVP

0.46

MPC

2.1

ClinPred

0.97

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.40

gMVP

0.84

Mutation Taster

=8/92

disease causing

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over