rs780594709

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_002180.3(IGHMBP2):c.1478C>T(p.Thr493Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000771 in 1,608,422 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T493A) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000082 ( 0 hom. )

Consequence

IGHMBP2
NM_002180.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10U:1

Conservation

PhyloP100: 7.15

Variant links:

Genes affected

IGHMBP2 (HGNC:5542): (immunoglobulin mu DNA binding protein 2) This gene encodes a helicase superfamily member that binds a specific DNA sequence from the immunoglobulin mu chain switch region. Mutations in this gene lead to spinal muscle atrophy with respiratory distress type 1. [provided by RefSeq, Jul 2008]

IGHMBP2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_002180.3

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-68933853-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 1426154.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.975

PP5

Variant 11-68933854-C-T is Pathogenic according to our data. Variant chr11-68933854-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 217450.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-68933854-C-T is described in Lovd as [Likely_pathogenic]. Variant chr11-68933854-C-T is described in Lovd as [Pathogenic]. Variant chr11-68933854-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IGHMBP2	NM_002180.3 linkuse as main transcript	c.1478C>T	p.Thr493Ile	missense_variant	10/15	ENST00000255078.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IGHMBP2	ENST00000255078.8 linkuse as main transcript	c.1478C>T	p.Thr493Ile	missense_variant	10/15	1	NM_002180.3	P1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000631

AC:

AN:

237608

Hom.:

AF XY:

0.0000388

AC XY:

AN XY:

128840

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000300

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000131

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000824

AC:

120

AN:

1456274

Hom.:

Cov.:

AF XY:

0.0000718

AC XY:

AN XY:

723830

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000227

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000105

Gnomad4 OTH exome

AF:

0.0000499

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152148

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74326

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000102

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.0000824

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jan 17, 2020	PS3, PS4_moderate, PM2, PM3, PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 27, 2021	Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19157874, 19158098, 22965130, 25439726, 27450922, 31827005, 18802676, 25454169) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 28, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Oct 05, 2017	- -

Autosomal recessive distal spinal muscular atrophy 1

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 20, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Oct 18, 2018	The IGHMBP2 c.1478C>T (p.Thr493Ile) missense variant has been reported in at least five studies in which it was identified in a compound heterozygous state in seven individuals from five families with spinal muscular atrophy (Guenther et al. 2009; Joseph et al. 2009; Eckart et al. 2012; Hamilton et al. 2015; Pedurupillay et al. 2016). In one sibling pair who carried a small deletion in trans with the p.Thr493Ile variant, one individual exhibited a more classic infantile spinal muscular atrophy phenotype while the other showed a phenotype consistent with Charcot-Marie-Tooth type 2S (Pedurupillay et al. 2016). However, the p.Thr493Ile variant was not identified in 11 probands with Charcot-Marie-Tooth type 2 who had recessively inherited IGHMBP2 variants (Cottenie et al. 2014). The variant p.Thr493Ile was absent from 300 control individuals (Guenther et al. 2009) and is reported at a frequency of 0.00025 in the European (non-Finnish) population of the Exome Aggregation Consortium. Expression of the variant in E. coli showed that it did not influence IGHMBP2 ATPase or helicase activity compared to wild type values (Guenther et al. 2009b), consistent with its location distant from helicase motifs. Comparison of steady-state IGHMBP2 protein levels in probands and their heterozygous parents indicated the p.Thr493Ile variant reduced steady-state protein levels by 50% compared to wild type levels (Guenther et al. 2009), and qRT-PCR experiments indicated the variant did not result in nonsense-mediated decay (Pedurupillay et al. 2016). Based on the collective evidence, the p.Thr493Ile variant is classified as pathogenic for spinal muscular atrophy. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Likely pathogenic, criteria provided, single submitter	research	Department of Medical Genetics, Oslo University Hospital	Oct 21, 2015	- -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 09, 2020

The p.T493I pathogenic mutation (also known as c.1478C>T), located in coding exon 10 of the IGHMBP2 gene, results from a C to T substitution at nucleotide position 1478. The threonine at codon 493 is replaced by isoleucine, an amino acid with similar properties. This alteration has been detected in trans with pathogenic mutations in IGHMBP2 in multiple affected individuals (Guenther UP et al. J. Mol. Med., 2009 Jan;87:31-41; Pedurupillay CR et al. Neuromuscul. Disord., 2016 09;26:570-5; Hamilton MJ et al. Neuromuscul. Disord., 2015 Feb;25:169-71). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Autosomal recessive distal spinal muscular atrophy 1;C4015349:Charcot-Marie-Tooth disease axonal type 2S

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 493 of the IGHMBP2 protein (p.Thr493Ile). This variant is present in population databases (rs780594709, gnomAD 0.01%). This missense change has been observed in individual(s) with spinal muscular atrophy with respiratory distress, type 1 or Charcot-Marie-Tooth disease, type 2S (PMID: 18802676, 19157874, 25454169, 27450922; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 217450). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on IGHMBP2 protein function. Experimental studies have shown that this missense change affects IGHMBP2 function (PMID: 18802676, 19158098). For these reasons, this variant has been classified as Pathogenic. -

Charcot-Marie-Tooth disease axonal type 2S

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Department of Medical Genetics, Oslo University Hospital

Oct 21, 2015

- -

Neuronopathy, distal hereditary motor, autosomal dominant

Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

Inherited Neuropathy Consortium

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.83

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.42

Cadd

Pathogenic

Dann

Uncertain

1.0

DEOGEN2

Uncertain

0.73

Eigen

Uncertain

0.66

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

M_CAP

Pathogenic

0.32

MetaRNN

Pathogenic

0.97

MetaSVM

Pathogenic

0.88

MutationAssessor

Uncertain

2.0

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.68

PROVEAN

Pathogenic

-5.4

REVEL

Pathogenic

0.93

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.046

Polyphen

1.0

Vest4

0.98

MVP

0.98

MPC

0.79

ClinPred

0.87

GERP RS

4.7

Varity_R

0.91

gMVP

0.90

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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

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