rs797044802

Positions:

• chr11-68908338-G-A
• chr11-68908338-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_002180.3(IGHMBP2):​c.449+1G>A variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: IGHMBP2 NM_002180.3 splice_donor
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.22

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 18 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-68908338-G-A is Pathogenic according to our data. Variant chr11-68908338-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 534927.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IGHMBP2	NM_002180.3	c.449+1G>A		splice_donor_variant		ENST00000255078.8	NP_002171.2
IGHMBP2	XM_005273976.3	c.449+1G>A		splice_donor_variant			XP_005274033.1
IGHMBP2	XM_017017671.3	c.449+1G>A		splice_donor_variant			XP_016873160.1
IGHMBP2	XM_047426881.1	c.449+1G>A		splice_donor_variant			XP_047282837.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IGHMBP2	ENST00000255078.8	c.449+1G>A		splice_donor_variant		1	NM_002180.3	ENSP00000255078	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

IGHMBP2-related disorder Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 24, 2024

The IGHMBP2 c.449+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant has been reported in the compound heterozygous state with an aberrant splicing IGHMBP2 deep intronic variant in an infant with spinal muscular atrophy with respiratory distress type 1 (SMARD1, Bodle et al. 2021. PubMed ID: 33189025). This variant has not been reported in a large population database, indicating this variant is rare. Variants that disrupt the consensus splice donor site in IGHMBP2 are expected to be pathogenic. Additionally, a different nucleotide change impacting the same GT donor site (c.449+1G>T) has been reported in the homozygous state in an infant with SMARD1 (Stalpers et al. 2013. PubMed ID: 23566544). This variant is interpreted as likely pathogenic. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 06, 2022

Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 534927). Disruption of this splice site has been observed in individuals with Charcot-Marie-Tooth disease (PMID: 25568292, 27450922). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 3 of the IGHMBP2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in IGHMBP2 are known to be pathogenic (PMID: 14681881, 25439726, 25568292). -

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

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 13, 2018

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Uncertain	-0.030
CADD	Pathogenic	32
DANN	Benign	0.97
Eigen	Pathogenic	0.73
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.99	D
MutationTaster	Benign	1.0	D;D
GERP RS		3.2

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.91
SpliceAI score (max)		0.83		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.83		Position offset: -1

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

Publications

LitVar

Other links and lift over

dbSNP: rs797044802; hg19: chr11-68675806;