Variant chr14-105855558-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The ENST00000637539.2(IGHM):c.571G>A(p.Gly191Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.888 in 777,510 control chromosomes in the GnomAD database, including 310,783 homozygotes. In-silico tool predicts a benign outcome for this variant. 4/4 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.84 ( 53939 hom., cov: 33)

Exomes 𝑓: 0.90 ( 256844 hom. )

Consequence

IGHM
ENST00000637539.2 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.148

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.48).

BP6

Variant 14-105855558-C-T is Benign according to our data. Variant chr14-105855558-C-T is described in ClinVar as [Benign]. Clinvar id is 2688227.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.928 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 linkuse as main transcript	c.571G>A	p.Gly191Ser	missense_variant	2/6			A2	P01871-2
IGHM	ENST00000390559.6 linkuse as main transcript	c.571G>A	p.Gly191Ser	missense_variant	2/4			P3	P01871-1

Frequencies

GnomAD3 genomes

AF:

0.837

AC:

125196

AN:

149642

Hom.:

53926

Cov.:

show subpopulations

Gnomad AFR

AF:

0.635

Gnomad AMI

AF:

0.979

Gnomad AMR

AF:

0.894

Gnomad ASJ

AF:

0.900

Gnomad EAS

AF:

0.592

Gnomad SAS

AF:

0.863

Gnomad FIN

AF:

0.964

Gnomad MID

AF:

0.831

Gnomad NFE

AF:

0.934

Gnomad OTH

AF:

0.846

GnomAD4 exome

AF:

0.901

AC:

565411

AN:

627798

Hom.:

256844

Cov.:

AF XY:

0.901

AC XY:

308025

AN XY:

342032

show subpopulations

Gnomad4 AFR exome

AF:

0.635

Gnomad4 AMR exome

AF:

0.917

Gnomad4 ASJ exome

AF:

0.888

Gnomad4 EAS exome

AF:

0.695

Gnomad4 SAS exome

AF:

0.869

Gnomad4 FIN exome

AF:

0.960

Gnomad4 NFE exome

AF:

0.934

Gnomad4 OTH exome

AF:

0.874

GnomAD4 genome

AF:

0.836

AC:

125221

AN:

149712

Hom.:

53939

Cov.:

AF XY:

0.839

AC XY:

61279

AN XY:

73012

show subpopulations

Gnomad4 AFR

AF:

0.635

Gnomad4 AMR

AF:

0.894

Gnomad4 ASJ

AF:

0.900

Gnomad4 EAS

AF:

0.592

Gnomad4 SAS

AF:

0.864

Gnomad4 FIN

AF:

0.964

Gnomad4 NFE

AF:

0.934

Gnomad4 OTH

AF:

0.840

Alfa

AF:

0.890

Hom.:

21936

Bravo

AF:

0.820

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Jan 24, 2024

This variant is classified as Benign based on local population frequency. This variant was detected in 98% of patients studied by a panel of primary immunodeficiencies. Number of patients: 93. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_noAF

Benign

-0.48

CADD

Benign

5.5

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over