chr14-105855041-A-G

Position:

• chr14-105855041-A-G

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.843T>C​(p.Thr281=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0171 in 778,228 control chromosomes in the GnomAD database, including 800 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.049 (540 hom., cov: 33)
  • Exomes 𝑓: 0.0096 (260 hom.)
• Consequence: IGHM ENST00000637539.2 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0270

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=-0.88).
• BP6: Variant 14-105855041-A-G is Benign according to our data. Variant chr14-105855041-A-G is described in ClinVar as [Benign]. Clinvar id is 810941.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.027 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.156 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.843T>C	p.Thr281=	synonymous_variant	3/6			A2
IGHM	ENST00000390559.6	c.843T>C	p.Thr281=	synonymous_variant	3/4			P3

Frequencies

GnomAD3 genomes AF: 0.0484 AC: 7268 AN: 150020 Hom.: 531 Cov.: 33

Gnomad AFR AF: 0.159

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0212

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00324

Gnomad FIN AF: 0.000942

Gnomad MID AF: 0.0259

Gnomad NFE AF: 0.00524

Gnomad OTH AF: 0.0399

GnomAD3 exomes AF: 0.0146 AC: 3580 AN: 245966 Hom.: 220 AF XY: 0.0122 AC XY: 1636 AN XY: 133662

Gnomad AFR exome AF: 0.162

Gnomad AMR exome AF: 0.0104

Gnomad ASJ exome AF: 0.000100

Gnomad EAS exome AF: 0.0000559

Gnomad SAS exome AF: 0.00281

Gnomad FIN exome AF: 0.000975

Gnomad NFE exome AF: 0.00507

Gnomad OTH exome AF: 0.0111

GnomAD4 exome AF: 0.00960 AC: 6032 AN: 628138 Hom.: 260 Cov.: 0 AF XY: 0.00851 AC XY: 2912 AN XY: 342202

Gnomad4 AFR exome AF: 0.159

Gnomad4 AMR exome AF: 0.0119

Gnomad4 ASJ exome AF: 0.000144

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00322

Gnomad4 FIN exome AF: 0.00136

Gnomad4 NFE exome AF: 0.00515

Gnomad4 OTH exome AF: 0.0164

GnomAD4 genome AF: 0.0485 AC: 7285 AN: 150090 Hom.: 540 Cov.: 33 AF XY: 0.0466 AC XY: 3412 AN XY: 73226

Gnomad4 AFR AF: 0.159

Gnomad4 AMR AF: 0.0212

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00282

Gnomad4 FIN AF: 0.000942

Gnomad4 NFE AF: 0.00524

Gnomad4 OTH AF: 0.0396

Alfa AF: 0.0254 Hom.: 116

Bravo AF: 0.0558

Asia WGS AF: 0.00907 AC: 31 AN: 3432

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

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	8.9
DANN	Benign	0.63

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs10287; hg19: chr14-106321146; COSMIC: COSV66666245;