rs770111639

Positions:

chr11-68935359-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_002180.3(IGHMBP2):c.1693G>A(p.Asp565Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000217 in 1,614,040 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: 𝑓 0.000026 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

IGHMBP2
NM_002180.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6U:1

Conservation

PhyloP100: 9.42

Variant links:

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 links:

IGHMBP2 (HGNC:):

IGHMBP2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.991

PP5

Variant 11-68935359-G-A is Pathogenic according to our data. Variant chr11-68935359-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 581680.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-68935359-G-A is described in Lovd as [Pathogenic]. Variant chr11-68935359-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IGHMBP2	NM_002180.3 linkuse as main transcript	c.1693G>A	p.Asp565Asn	missense_variant	12/15	ENST00000255078.8	NP_002171.2	P38935

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IGHMBP2	ENST00000255078.8 linkuse as main transcript	c.1693G>A	p.Asp565Asn	missense_variant	12/15	1	NM_002180.3	ENSP00000255078.4		P38935

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152260

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000239

AC:

AN:

251404

Hom.:

AF XY:

0.0000294

AC XY:

AN XY:

135900

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000212

AC:

AN:

1461780

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

727200

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000225

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152260

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74382

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000324

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 14, 2023	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 565 of the IGHMBP2 protein (p.Asp565Asn). This variant is present in population databases (rs770111639, gnomAD 0.01%). This missense change has been observed in individual(s) with distal hereditary motor neuropathy, type VI (PMID: 14681881, 15108294, 22157136). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 581680). 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 expected to disrupt IGHMBP2 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects IGHMBP2 function (PMID: 19158098, 22157136). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 07, 2024	- -

Charcot-Marie-Tooth disease axonal type 2S

Pathogenic:2

Likely pathogenic, no assertion criteria provided	case-control	Biochemistry Laboratory of CDMU, Chengde Medical University	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 01, 2024	Variant summary: IGHMBP2 c.1693G>A (p.Asp565Asn) results in a conservative amino acid change located in the DNA2/NAM7 helicase-like, C-terminal domain (IPR041679) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251404 control chromosomes. c.1693G>A has been reported in the literature in at-least two individuals affected with Charcot-Marie-Tooth Disease, Axonal, Type 2S and Spinal Muscular Atrophy with Respiratory Distress (examples, Maystadt_2004, Xiao_2022, Gao_2019). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in completely inactive in the helicase assay, but still retained its full nucleic acid binding capacity in FM3A cells (Guenther_2009). The following publications have been ascertained in the context of this evaluation (PMID: 34986626, 31178897, 19158098, 15108294). ClinVar contains an entry for this variant (Variation ID: 581680). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Inborn genetic diseases

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 12, 2021

The c.1693G>A (p.D565N) alteration is located in exon 12 (coding exon 12) of the IGHMBP2 gene. This alteration results from a G to A substitution at nucleotide position 1693, causing the aspartic acid (D) at amino acid position 565 to be replaced by an asparagine (N). Based on data from the Genome Aggregation Database (gnomAD) database, the IGHMBP2 c.1693G>A alteration was observed in 0.002% (7/282810) of total alleles studied, with a frequency of 0.01% (1/10370) in the Ashkenazi Jewish subpopulation. This alteration has been reported in trans with a pathogenic alteration in an individual with spinal muscular atrophy 1 with respiratory distress (SMARD1) (Maystadt, 2004). It was also reported in trans with a different alteration in a child with developmental delay, motor deterioration, myotonia, reduced tendon reflexes, slurred speech, abnormal posturing, poor fine motor coordination, peripheral neuropathy, talipes equinovarus, and EMG abnormality (Gao, 2019). This amino acid position is highly conserved in available vertebrate species. This alteration has also been shown to impair protein function (Eckart, 2012; Guenther, 2009). The in silico prediction for the p.D565N alteration is inconclusive. Based on the available evidence, this alteration is classified as likely pathogenic. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

May 01, 2023

IGHMBP2: PM3:Very Strong, PM2, PP3, PS3:Supporting -

Distal spinal muscular atrophy

Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

Inherited Neuropathy Consortium

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Pathogenic

0.14

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.89

Eigen

Pathogenic

0.86

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

M_CAP

Pathogenic

0.53

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.1

PrimateAI

Uncertain

0.72

PROVEAN

Pathogenic

-4.7

REVEL

Pathogenic

0.86

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.94

MutPred

0.92

Loss of ubiquitination at K562 (P = 0.0755);

MVP

0.97

MPC

0.75

ClinPred

1.0

GERP RS

5.0

Varity_R

0.95

gMVP

0.83

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over