chr19-41878986-ACAGGCCCTGGGTGC-A

Variant names:

• chr19-41878986-ACAGGCCCTGGGTGC-A
• NM_001783.4:c.86_99delGGTGCCAGGCCCTG

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Strong PP5_Moderate

The ENST00000221972.8(CD79A):​c.80-3_90delCAGGCCCTGGGTGC​(p.Gly27fs) variant causes a frameshift, splice acceptor, splice region, intron change. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. G27G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CD79A ENST00000221972.8 frameshift, splice_acceptor, splice_region, intron
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.02
• Publications: 0 publications found

Genes affected

CD79A (HGNC:1698): (CD79a molecule) The B lymphocyte antigen receptor is a multimeric complex that includes the antigen-specific component, surface immunoglobulin (Ig). Surface Ig non-covalently associates with two other proteins, Ig-alpha and Ig-beta, which are necessary for expression and function of the B-cell antigen receptor. This gene encodes the Ig-alpha protein of the B-cell antigen component. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jul 2008]

CD79A Gene-Disease associations (from GenCC):

• agammaglobulinemia 3, autosomal recessive

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen
• autosomal agammaglobulinemia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.883 CDS is truncated, and there are 3 pathogenic variants in the truncated region.
• PP5: Variant 19-41878986-ACAGGCCCTGGGTGC-A is Pathogenic according to our data. Variant chr19-41878986-ACAGGCCCTGGGTGC-A is described in ClinVar as [Pathogenic]. Clinvar id is 2128215.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CD79A	NM_001783.4	c.86_99delGGTGCCAGGCCCTG	p.Gly29fs	frameshift_variant	Exon 2 of 5	ENST00000221972.8	NP_001774.1
CD79A	NM_021601.4	c.86_99delGGTGCCAGGCCCTG	p.Gly29fs	frameshift_variant	Exon 2 of 5		NP_067612.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CD79A	ENST00000221972.8	c.80-3_90delCAGGCCCTGGGTGC	p.Gly27fs	frameshift_variant, splice_acceptor_variant, splice_region_variant, intron_variant	Exon 2 of 5	1	NM_001783.4	ENSP00000221972.3
CD79A	ENST00000444740.2	c.80-3_90delCAGGCCCTGGGTGC	p.Gly27fs	frameshift_variant, splice_acceptor_variant, splice_region_variant, intron_variant	Exon 2 of 5	1		ENSP00000400605.1
CD79A	ENST00000597454.2	c.80-3_90delCAGGCCCTGGGTGC	p.Gly27fs	frameshift_variant, splice_acceptor_variant, splice_region_variant, intron_variant	Exon 2 of 4	3		ENSP00000468922.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 911516 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 463704

African (AFR) AF: 0.00 AC: 0 AN: 21064

American (AMR) AF: 0.00 AC: 0 AN: 37870

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16224

East Asian (EAS) AF: 0.00 AC: 0 AN: 19192

South Asian (SAS) AF: 0.00 AC: 0 AN: 77256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30714

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4048

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 669840

Other (OTH) AF: 0.00 AC: 0 AN: 35308

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Agammaglobulinemia 3, autosomal recessive Pathogenic:1

Apr 20, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant has not been reported in the literature in individuals affected with CD79A-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gly29Valfs*25) in the CD79A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CD79A are known to be pathogenic (PMID: 10525050, 24481606). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.0

Splicing

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

Other links and lift over

hg19: chr19-42383056;