rs1555247438

Variant names:

• chr11-68934001-G-A
• rs1555247438
• NM_002180.3:c.1537+88G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_002180.3(IGHMBP2):​c.1537+88G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000106 in 943,898 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: IGHMBP2 NM_002180.3 intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.519
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• autosomal recessive distal spinal muscular atrophy 1

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Ambry Genetics, Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)
• Charcot-Marie-Tooth disease axonal type 2S

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• hereditary peripheral neuropathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGHMBP2	NM_002180.3	c.1537+88G>A		intron_variant	Intron 10 of 14	ENST00000255078.8	NP_002171.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IGHMBP2	ENST00000255078.8	c.1537+88G>A		intron_variant	Intron 10 of 14	1	NM_002180.3	ENSP00000255078.4

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152226 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000101 AC: 8 AN: 791672 Hom.: 0 Cov.: 10 AF XY: 0.0000121 AC XY: 5 AN XY: 412316

African (AFR) AF: 0.0000499 AC: 1 AN: 20034

American (AMR) AF: 0.00 AC: 0 AN: 34810

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21420

East Asian (EAS) AF: 0.000122 AC: 4 AN: 32860

South Asian (SAS) AF: 0.00 AC: 0 AN: 66542

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48184

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4486

European-Non Finnish (NFE) AF: 0.00000571 AC: 3 AN: 525248

Other (OTH) AF: 0.00 AC: 0 AN: 38088

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152226 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74382

African (AFR) AF: 0.00 AC: 0 AN: 41452

American (AMR) AF: 0.0000654 AC: 1 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5206

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal recessive distal spinal muscular atrophy 1 Uncertain:1

Jan 21, 2018

Service de Pédiatrie - Neurologie et infectiologie - Toulouse, CHU de Toulouse - Hôpital des Enfants

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: case-control

Never published in databases. It is a deep intronic mutation probably affecting a splice donor site, which dysfunction might generate a premature codon stop. It occurs at the middle in the sequence: in the intron 10, for a total of 15 exons. It is located in the main functional domain of the protein IGHMB2 the "DNA helicase domain", at a specific location where ATP binding sites are concentrated (region 2A). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Pathogenic	28
DANN	Benign	0.76
PhyloP100		0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.98		Position offset: 2

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

Other links and lift over

dbSNP: rs1555247438; hg19: chr11-68701469; COSMIC: COSV54820163; COSMIC: COSV54820163;