rs281865422

Positions:

• chr14-105855107-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The ENST00000637539.2(IGHM):​c.777G>A​(p.Trp259*) variant causes a stop gained change. 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 Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: IGHM ENST00000637539.2 stop_gained
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 4.40

Genes affected

IGHM (HGNC:5541): (immunoglobulin heavy constant mu) Immunoglobulins (Ig) are the antigen recognition molecules of B cells. An Ig molecule is made up of 2 identical heavy chains and 2 identical light chains (see MIM 147200) joined by disulfide bonds so that each heavy chain is linked to a light chain and the 2 heavy chains are linked together. Each Ig heavy chain has an N-terminal variable (V) region containing the antigen-binding site and a C-terminal constant (C) region, encoded by an individual C region gene, that determines the isotype of the antibody and provides effector or signaling functions. The heavy chain V region is encoded by 1 each of 3 types of genes: V genes (see MIM 147070), joining (J) genes (see MIM 147010), and diversity (D) genes (see MIM 146910). The C region genes are clustered downstream of the V region genes within the heavy chain locus on chromosome 14. The IGHM gene encodes the C region of the mu heavy chain, which defines the IgM isotype. Naive B cells express the transmembrane forms of IgM and IgD (see IGHD; MIM 1471770) on their surface. During an antibody response, activated B cells can switch to the expression of individual downstream heavy chain C region genes by a process of somatic recombination known as isotype switching. In addition, secreted Ig forms that act as antibodies can be produced by alternative RNA processing of the heavy chain C region sequences. Although the membrane forms of all Ig isotypes are monomeric, secreted IgM forms pentamers, and occasionally hexamers, in plasma (summary by Janeway et al., 2005).[supplied by OMIM, Aug 2010]

IGHM (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 14-105855107-C-T is Pathogenic according to our data. Variant chr14-105855107-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 14813.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IGHM	unassigned_transcript_2480	c.774G>A	p.Trp258*	stop_gained	3/4
IGHM	unassigned_transcript_2479	c.776G>A	p.Gly259Glu	missense_variant	3/6
IGH		n.105855107C>T		intragenic_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IGHM	ENST00000637539.2	c.777G>A	p.Trp259*	stop_gained	3/6	6		ENSP00000490253.1
IGHM	ENST00000390559.6	c.777G>A	p.Trp259*	stop_gained	3/4	6		ENSP00000375001.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Autosomal recessive agammaglobulinemia 1 Pathogenic:1 Other:1

not provided, no classification provided	literature only	ClinVar Staff, National Center for Biotechnology Information (NCBI)	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 2002	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	40
DANN	Uncertain	1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs281865422; hg19: chr14-106321212; COSMIC: COSV101163789;