chr14-105855203-G-A

Position:

• chr14-105855203-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The ENST00000637539.2(IGHM):​c.681C>T​(p.Ile227=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0112 in 778,212 control chromosomes in the GnomAD database, including 285 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.029 (186 hom., cov: 33)
  • Exomes 𝑓: 0.0069 (99 hom.)
• Consequence: IGHM ENST00000637539.2 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.54

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]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 14-105855203-G-A is Benign according to our data. Variant chr14-105855203-G-A is described in ClinVar as [Benign]. Clinvar id is 2428589.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-1.54 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0891 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IGHM	ENST00000637539.2	c.681C>T	p.Ile227=	synonymous_variant	3/6			A2
IGHM	ENST00000390559.6	c.681C>T	p.Ile227=	synonymous_variant	3/4			P3

Frequencies

GnomAD3 genomes AF: 0.0291 AC: 4366 AN: 150062 Hom.: 178 Cov.: 33

Gnomad AFR AF: 0.0914

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0152

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00259

Gnomad FIN AF: 0.000942

Gnomad MID AF: 0.0202

Gnomad NFE AF: 0.00491

Gnomad OTH AF: 0.0288

GnomAD3 exomes AF: 0.00951 AC: 2341 AN: 246116 Hom.: 81 AF XY: 0.00841 AC XY: 1124 AN XY: 133728

Gnomad AFR exome AF: 0.0907

Gnomad AMR exome AF: 0.00717

Gnomad ASJ exome AF: 0.000100

Gnomad EAS exome AF: 0.0000558

Gnomad SAS exome AF: 0.00275

Gnomad FIN exome AF: 0.000929

Gnomad NFE exome AF: 0.00488

Gnomad OTH exome AF: 0.00914

GnomAD4 exome AF: 0.00691 AC: 4338 AN: 628080 Hom.: 99 Cov.: 0 AF XY: 0.00645 AC XY: 2206 AN XY: 342186

Gnomad4 AFR exome AF: 0.0887

Gnomad4 AMR exome AF: 0.00840

Gnomad4 ASJ exome AF: 0.000144

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00301

Gnomad4 FIN exome AF: 0.00134

Gnomad4 NFE exome AF: 0.00487

Gnomad4 OTH exome AF: 0.0112

GnomAD4 genome AF: 0.0292 AC: 4382 AN: 150132 Hom.: 186 Cov.: 33 AF XY: 0.0281 AC XY: 2059 AN XY: 73242

Gnomad4 AFR AF: 0.0916

Gnomad4 AMR AF: 0.0152

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00260

Gnomad4 FIN AF: 0.000942

Gnomad4 NFE AF: 0.00491

Gnomad4 OTH AF: 0.0286

Alfa AF: 0.0158 Hom.: 36

Bravo AF: 0.0334

Asia WGS AF: 0.00703 AC: 24 AN: 3428

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal recessive agammaglobulinemia 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Sep 13, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	1.5
DANN	Benign	0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs113517608; hg19: chr14-106321308;