rs281865422

Variant names:

• chr14-105855107-C-T
• rs281865422
• ENST00000637539.2:c.777G>A
• IGHM p.Trp259*

Variant summary

Our verdict is Pathogenic. The variant received 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
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• autosomal recessive agammaglobulinemia 1

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

IGH (HGNC:5477):

ACMG classification

Our verdict: Pathogenic. The variant received 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 VariationId is 14813.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000637539.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
There are no transcript annotations for this variant.

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IGHM	ENST00000637539.2	TSL:6	c.777G>A	p.Trp259*	stop_gained	Exon 3 of 6	ENSP00000490253.1	P01871-2
	IGHM	ENST00000390559.6	TSL:6	c.777G>A	p.Trp259*	stop_gained	Exon 3 of 4	ENSP00000375001.2	P01871-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Autosomal recessive agammaglobulinemia 1 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	40
DANN	Uncertain	1.0
PhyloP100		4.4

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs281865422;

hg19: chr14-106321212;

COSMIC: COSV101163789;