rs3750320

Variant names:

• chr9-128908178-T-C
• rs3750320
• NM_019594.4:c.1014T>C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_019594.4(LRRC8A):​c.1014T>C​(p.Tyr338Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.195 in 1,613,768 control chromosomes in the GnomAD database, including 33,853 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.24 (5162 hom., cov: 31)
  • Exomes 𝑓: 0.19 (28691 hom.)
• Consequence: LRRC8A NM_019594.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.78

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 9-128908178-T-C is Benign according to our data. Variant chr9-128908178-T-C is described in ClinVar as [Benign]. Clinvar id is 403060.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.78 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.394 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRRC8A	NM_019594.4	c.1014T>C	p.Tyr338Tyr	synonymous_variant	Exon 3 of 4	ENST00000372600.9	NP_062540.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRRC8A	ENST00000372600.9	c.1014T>C	p.Tyr338Tyr	synonymous_variant	Exon 3 of 4	1	NM_019594.4	ENSP00000361682.4
LRRC8A	ENST00000372599.7	c.1014T>C	p.Tyr338Tyr	synonymous_variant	Exon 2 of 3	1		ENSP00000361680.3
LRRC8A	ENST00000259324.5	c.1014T>C	p.Tyr338Tyr	synonymous_variant	Exon 3 of 4	2		ENSP00000259324.5

Frequencies

GnomAD3 genomes AF: 0.239 AC: 36369 AN: 151884 Hom.: 5158 Cov.: 31

Gnomad AFR AF: 0.399

Gnomad AMI AF: 0.132

Gnomad AMR AF: 0.168

Gnomad ASJ AF: 0.193

Gnomad EAS AF: 0.192

Gnomad SAS AF: 0.290

Gnomad FIN AF: 0.126

Gnomad MID AF: 0.288

Gnomad NFE AF: 0.179

Gnomad OTH AF: 0.251

GnomAD3 exomes AF: 0.197 AC: 49560 AN: 251302 Hom.: 5590 AF XY: 0.201 AC XY: 27368 AN XY: 135850

Gnomad AFR exome AF: 0.409

Gnomad AMR exome AF: 0.122

Gnomad ASJ exome AF: 0.206

Gnomad EAS exome AF: 0.170

Gnomad SAS exome AF: 0.287

Gnomad FIN exome AF: 0.127

Gnomad NFE exome AF: 0.182

Gnomad OTH exome AF: 0.203

GnomAD4 exome AF: 0.191 AC: 278756 AN: 1461766 Hom.: 28691 Cov.: 35 AF XY: 0.194 AC XY: 140740 AN XY: 727170

Gnomad4 AFR exome AF: 0.413

Gnomad4 AMR exome AF: 0.129

Gnomad4 ASJ exome AF: 0.205

Gnomad4 EAS exome AF: 0.212

Gnomad4 SAS exome AF: 0.288

Gnomad4 FIN exome AF: 0.124

Gnomad4 NFE exome AF: 0.180

Gnomad4 OTH exome AF: 0.207

GnomAD4 genome AF: 0.239 AC: 36395 AN: 152002 Hom.: 5162 Cov.: 31 AF XY: 0.237 AC XY: 17606 AN XY: 74278

Gnomad4 AFR AF: 0.399

Gnomad4 AMR AF: 0.167

Gnomad4 ASJ AF: 0.193

Gnomad4 EAS AF: 0.191

Gnomad4 SAS AF: 0.290

Gnomad4 FIN AF: 0.126

Gnomad4 NFE AF: 0.179

Gnomad4 OTH AF: 0.248

Alfa AF: 0.197 Hom.: 5311

Bravo AF: 0.249

Asia WGS AF: 0.201 AC: 697 AN: 3478

EpiCase AF: 0.191

EpiControl AF: 0.200

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Agammaglobulinemia 5, autosomal dominant Benign:1

Aug 19, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	8.9
DANN	Benign	0.43

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

LitVar

Other links and lift over

dbSNP: rs3750320; hg19: chr9-131670457; COSMIC: COSV52185470; COSMIC: COSV52185470;