rs368775789

Positions:

• chr11-68935403-C-A
• chr11-68935403-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 12P and 1B. PM1 PM2 PP5_Very_Strong BP4

The NM_002180.3(IGHMBP2):​c.1737C>A​(p.Phe579Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,726 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign 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. F579C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: IGHMBP2 NM_002180.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: -1.59

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]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_002180.3
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-68935403-C-A is Pathogenic according to our data. Variant chr11-68935403-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 245630.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.10517368). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IGHMBP2	NM_002180.3	c.1737C>A	p.Phe579Leu	missense_variant	12/15	ENST00000255078.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IGHMBP2	ENST00000255078.8	c.1737C>A	p.Phe579Leu	missense_variant	12/15	1	NM_002180.3	P1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461726 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727172

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 18, 2023

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) performed at Invitae indicates that this missense variant is not expected to disrupt IGHMBP2 protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 245630). This missense change has been observed in individual(s) with clinical features of IGHMBP2-related conditions (PMID: 28065684, 29653221). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 579 of the IGHMBP2 protein (p.Phe579Leu). -

Autosomal recessive distal spinal muscular atrophy 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

-

- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 25, 2016

The F579L missense variant in the IGHMBP2 gene was not observed in approximately 6,400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. It is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties and in silico analysis predicts this variant likely does not alter the protein structure. However, this substitution occurs at a position where amino acids with similar properties to Phenylalanine are tolerated across species. In addition, this variant is predicted to be within the helicase domain where other missense variants in nearby residues have been reported in the Human Gene Mutation Database in association with SMARD1 (Stenson et al., 2014), supporting the functional importance of this region of the protein. Based on the current ACMG guidelines, this variant is considered likely pathogenic; however, the possibility that it is benign cannot be complete excluded. -

Charcot-Marie-Tooth disease axonal type 2S Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 10, 2023

Variant summary: IGHMBP2 c.1737C>A (p.Phe579Leu) results in a non-conservative amino acid change located in the DNA2/NAM7 helicase-like, C-terminal (IPR041679) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251420 control chromosomes. c.1737C>A has been reported in the literature in an individual(s) affected with Charcot-Marie-Tooth Disease (Xie_2021), as well as in individuals with Spinal muscular atrophy with respiratory distress 1 (Wu_2018, Baughn_2011, Luan_2016), some of which were reported as compound heterozygous with (likely) pathogenic variants. These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 34255403, 29653221, 21360834, 26922252). One submitter has cited a clinical-significance assessment for this variant to ClinVar after 2014 and has classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	3.5
DANN	Benign	0.84
DEOGEN2	Benign	0.33	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.21	N
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-1.4	N
MutationTaster	Benign	0.99	D
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.29	N
REVEL	Benign	0.16
Sift	Benign	0.88	T
Sift4G	Benign	1.0	T
Polyphen		0.0090	B
Vest4		0.17
MutPred		0.52		Gain of sheet (P = 0.1208);
MVP		0.34
MPC		0.23
ClinPred		0.66	D
GERP RS		-0.85
Varity_R		0.14
gMVP		0.55

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: rs368775789; hg19: chr11-68702871;