chr17-63929439-A-G

Position:

• chr17-63929439-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

The NM_000626.4(CD79B):​c.586T>C​(p.Tyr196His) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,674 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CD79B NM_000626.4 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 4.90

Genes affected

CD79B (HGNC:1699): (CD79b 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-beta protein of the B-cell antigen component. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a modified_residue Phosphotyrosine; by SRC-type Tyr-kinases (size 0) in uniprot entity CD79B_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.844
• PP5: Variant 17-63929439-A-G is Pathogenic according to our data. Variant chr17-63929439-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2573989.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CD79B	NM_000626.4	c.586T>C	p.Tyr196His	missense_variant	5/6	ENST00000006750.8	NP_000617.1
CD79B	NM_001039933.3	c.589T>C	p.Tyr197His	missense_variant	5/6		NP_001035022.1
CD79B	NM_001329050.2	c.277T>C	p.Tyr93His	missense_variant	4/5		NP_001315979.1
CD79B	NM_021602.4	c.274T>C	p.Tyr92His	missense_variant	4/5		NP_067613.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CD79B	ENST00000006750.8	c.586T>C	p.Tyr196His	missense_variant	5/6	1	NM_000626.4	ENSP00000006750	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461674 Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3 AN XY: 727136

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Malignant lymphoma, large B-cell, diffuse Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Wasik Lab, Fox Chase Cancer Center

Jul 25, 2023

This variant was observed in a patient with DLBCL that presented in leukemic form, best classified as MCD/C5 DLBCL, an ABC subtype. Despite an initial good clinical response to BTK inhibitor ibrutinib, anti-CD20 antibody rituxan, alkylating agent bendamustine, and hematopoietic stem-cell transplant, the lymphoma relapsed, accompanied by morphologic and molecular evidence of disease progression. At presentation and relapse, hallmark genomic changes affecting chronic active B-cell and Toll-like receptor (TLR) signaling pathways were present. These changes promote constitutive activation of NF-kB, a transcription factor which regulates many genes that drive B-cell proliferation and survival (Baldwin 2001). B-cell clonality studies identified a dominant B-cell clone with heavy chain IGHV4-34; IGHD3-16; IGHJ4. This variant is present in one-third of ABC DLBC cases and plays an important role in initiation and perpetuation of BCR signaling. The signaling initiation is proposed to result from binding of self antigens such as glycoproteins with N-acetyl-lactosamine sugars, driving chronic active BCR signaling (Young et al. 2019). Mutation of the BCR component CD79B Y196H was seen initially. At relapse, this variant was accompanied by DNA copy number gain associated with increased RNA expression, strongly suggestive of an oncogenic role. Mutations affecting the ITAM motifs of either CD79A or CD79B are present in ~30% of ABC DLBCL (Young et al. 2019), with the CD79B Y196H mutation being one of the most frequent. The Y196H mutation eliminates the phosphorylation site of the first ITAM, which is thought to impair BCR internalization, resulting in sustained BCR signaling (Baldwin 2001) and proliferation of malignant B cells. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	.;D;.
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.84	T;T;D
M_CAP	Pathogenic	0.44	D
MetaRNN	Pathogenic	0.84	D;D;D
MetaSVM	Pathogenic	0.85	D
MutationAssessor	Benign	0.69	.;N;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-3.9	D;D;D
REVEL	Pathogenic	0.75
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		1.0, 1.0	.;D;D
Vest4		0.78
MutPred		0.64		.;Loss of phosphorylation at Y196 (P = 0.0116);.;
MVP		0.86
MPC		1.7
ClinPred		0.98	D
GERP RS		4.2
Varity_R		0.69
gMVP		0.84

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: rs1907977856; hg19: chr17-62006799; COSMIC: COSV50075971; COSMIC: COSV50075971;