rs886037759

Variant names:

• chr11-68903954-T-C
• rs886037759
• NM_002180.3:c.2T>C

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.2T>C​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000141 in 1,416,214 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 (★★).

• Frequency:
  • Genomes: not found (cov: 35)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: IGHMBP2 NM_002180.3 start_lost
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 0.610

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]

MRPL21 (HGNC:14479): (mitochondrial ribosomal protein L21) Mammalian mitochondrial ribosomal proteins are encoded by nuclear genes and help in protein synthesis within the mitochondrion. Mitochondrial ribosomes (mitoribosomes) consist of a small 28S subunit and a large 39S subunit. They have an estimated 75% protein to rRNA composition compared to prokaryotic ribosomes, where this ratio is reversed. Another difference between mammalian mitoribosomes and prokaryotic ribosomes is that the latter contain a 5S rRNA. Among different species, the proteins comprising the mitoribosome differ greatly in sequence, and sometimes in biochemical properties, which prevents easy recognition by sequence homology. This gene encodes a 39S subunit protein. Multiple transcript variants encoding different isoforms were identified through sequence analysis although some may be subject to nonsense-mediated decay (NMD). [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 36 pathogenic variants. Next in-frame start position is after 338 codons. Genomic position: 68917835. Lost 0.339 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-68903954-T-C is Pathogenic according to our data. Variant chr11-68903954-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 217448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-68903954-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGHMBP2	NM_002180.3	c.2T>C	p.Met1?	start_lost	Exon 1 of 15	ENST00000255078.8	NP_002171.2
MRPL21	NM_181514.2	c.-144A>G		upstream_gene_variant		ENST00000362034.7	NP_852615.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IGHMBP2	ENST00000255078.8	c.2T>C	p.Met1?	start_lost	Exon 1 of 15	1	NM_002180.3	ENSP00000255078.4
MRPL21	ENST00000362034.7	c.-144A>G		upstream_gene_variant		1	NM_181514.2	ENSP00000354580.2

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD4 exome AF: 0.00000141 AC: 2 AN: 1416214 Hom.: 0 Cov.: 46 AF XY: 0.00000143 AC XY: 1 AN XY: 700874

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000243

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 35

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

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

Aug 04, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Disruption of the initiator codon has been observed in individuals with Charcot-Marie-Tooth disease or spinal muscular atrophy with respiratory distress (PMID: 26392352, 27450922). This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the IGHMBP2 mRNA. The next in-frame methionine is located at codon 338. This variant disrupts a region of the IGHMBP2 protein in which other variant(s) (p.Gly61Arg) have been determined to be pathogenic (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 217448). -

Inborn genetic diseases Pathogenic:1

Jun 02, 2015

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive distal spinal muscular atrophy 1 Pathogenic:1

Oct 21, 2015

Department of Medical Genetics, Oslo University Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.23
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.13	T;.
Eigen	Uncertain	0.19
Eigen_PC	Benign	0.18
FATHMM_MKL	Benign	0.081	N
LIST_S2	Uncertain	0.90	D;D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Uncertain	0.16	D
PROVEAN	Benign	-1.4	N;N
REVEL	Uncertain	0.64
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.0080	D;D
Polyphen		0.96	D;.
Vest4		0.73
MutPred		1.0		Gain of catalytic residue at M1 (P = 0.0064);Gain of catalytic residue at M1 (P = 0.0064);
MVP		0.98
ClinPred		1.0	D
GERP RS		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.95
gMVP		0.61

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

Other links and lift over

dbSNP: rs886037759; hg19: chr11-68671422;