rs118015540

Positions:

• chr11-68906247-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002180.3(IGHMBP2):​c.256+9G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00773 in 1,613,624 control chromosomes in the GnomAD database, including 63 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0057 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0079 (59 hom.)
• Consequence: IGHMBP2 NM_002180.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.797

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 11-68906247-G-A is Benign according to our data. Variant chr11-68906247-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 137568.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-68906247-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00567 (863/152306) while in subpopulation NFE AF= 0.00938 (638/68026). AF 95% confidence interval is 0.00878. There are 4 homozygotes in gnomad4. There are 386 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IGHMBP2	NM_002180.3	c.256+9G>A		intron_variant		ENST00000255078.8	NP_002171.2
IGHMBP2	XM_047426881.1	c.256+9G>A		intron_variant			XP_047282837.1
IGHMBP2	XM_017017671.3	c.256+9G>A		intron_variant			XP_016873160.1
IGHMBP2	XM_005273976.3	c.256+9G>A		intron_variant			XP_005274033.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IGHMBP2	ENST00000255078.8	c.256+9G>A		intron_variant		1	NM_002180.3	ENSP00000255078.4

Frequencies

GnomAD3 genomes AF: 0.00567 AC: 863 AN: 152188 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00176

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00543

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00500

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00938

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00508 AC: 1277 AN: 251290 Hom.: 6 AF XY: 0.00511 AC XY: 694 AN XY: 135828

Gnomad AFR exome AF: 0.00234

Gnomad AMR exome AF: 0.00298

Gnomad ASJ exome AF: 0.000893

Gnomad EAS exome AF: 0.000326

Gnomad SAS exome AF: 0.000817

Gnomad FIN exome AF: 0.00476

Gnomad NFE exome AF: 0.00836

Gnomad OTH exome AF: 0.00701

GnomAD4 exome AF: 0.00795 AC: 11612 AN: 1461318 Hom.: 59 Cov.: 30 AF XY: 0.00777 AC XY: 5648 AN XY: 727022

Gnomad4 AFR exome AF: 0.00126

Gnomad4 AMR exome AF: 0.00333

Gnomad4 ASJ exome AF: 0.00142

Gnomad4 EAS exome AF: 0.000202

Gnomad4 SAS exome AF: 0.000846

Gnomad4 FIN exome AF: 0.00511

Gnomad4 NFE exome AF: 0.00960

Gnomad4 OTH exome AF: 0.00573

GnomAD4 genome AF: 0.00567 AC: 863 AN: 152306 Hom.: 4 Cov.: 32 AF XY: 0.00518 AC XY: 386 AN XY: 74476

Gnomad4 AFR AF: 0.00176

Gnomad4 AMR AF: 0.00543

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00500

Gnomad4 NFE AF: 0.00938

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00694 Hom.: 1

Bravo AF: 0.00574

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 07, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 12, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Autosomal recessive distal spinal muscular atrophy 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Jul 28, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2024	IGHMBP2: BS2 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 01, 2023	- -

Charcot-Marie-Tooth disease Benign:1

Benign, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

-

- -

IGHMBP2-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 19, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.2
DANN	Benign	0.94
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs118015540; hg19: chr11-68673715;