rs35610053

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_002180.3(IGHMBP2):c.304G>T(p.Ala102Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00032 in 1,614,026 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A102D) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0017 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00018 ( 3 hom. )

Consequence

IGHMBP2
NM_002180.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:6

Conservation

PhyloP100: 3.55

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008548826).

BP6

Variant 11-68908192-G-T is Benign according to our data. Variant chr11-68908192-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 466594.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=6}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00166 (253/152142) while in subpopulation AFR AF= 0.00542 (225/41496). AF 95% confidence interval is 0.00484. There are 0 homozygotes in gnomad4. There are 111 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
IGHMBP2	NM_002180.3 linkuse as main transcript	c.304G>T	p.Ala102Ser	missense_variant	3/15	ENST00000255078.8
IGHMBP2	XM_047426881.1 linkuse as main transcript	c.304G>T	p.Ala102Ser	missense_variant	3/15
IGHMBP2	XM_017017671.3 linkuse as main transcript	c.304G>T	p.Ala102Ser	missense_variant	3/12
IGHMBP2	XM_005273976.3 linkuse as main transcript	c.304G>T	p.Ala102Ser	missense_variant	3/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IGHMBP2	ENST00000255078.8 linkuse as main transcript	c.304G>T	p.Ala102Ser	missense_variant	3/15	1	NM_002180.3	P1

Frequencies

GnomAD3 genomes

AF:

0.00165

AC:

251

AN:

152024

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00539

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00170

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:

0.00

Gnomad OTH

AF:

0.000959

GnomAD3 exomes

AF:

0.000489

AC:

123

AN:

251468

Hom.:

AF XY:

0.000294

AC XY:

AN XY:

135908

show subpopulations

Gnomad AFR exome

AF:

0.00578

Gnomad AMR exome

AF:

0.000752

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000181

AC:

264

AN:

1461884

Hom.:

Cov.:

AF XY:

0.000133

AC XY:

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.00550

Gnomad4 AMR exome

AF:

0.000738

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.000712

GnomAD4 genome

AF:

0.00166

AC:

253

AN:

152142

Hom.:

Cov.:

AF XY:

0.00149

AC XY:

111

AN XY:

74374

show subpopulations

Gnomad4 AFR

AF:

0.00542

Gnomad4 AMR

AF:

0.00170

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000949

Alfa

AF:

0.000315

Hom.:

Bravo

AF:

0.00197

ESP6500AA

AF:

0.00591

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000478

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 30, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 22, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2022	IGHMBP2: PM2 -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -

IGHMBP2-related condition

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 09, 2020

This variant is classified as likely 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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 11, 2020

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.12

Cadd

Benign

Dann

Uncertain

0.99

DEOGEN2

Benign

0.11

T;.

Eigen

Benign

-0.16

Eigen_PC

Benign

-0.039

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.83

T;T

M_CAP

Benign

0.053

MetaRNN

Benign

0.0085

T;T

MetaSVM

Uncertain

-0.070

MutationAssessor

Benign

1.0

L;.

MutationTaster

Benign

0.62

D;D

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-0.89

N;N

REVEL

Uncertain

0.39

Sift

Benign

0.28

T;T

Sift4G

Benign

0.42

T;T

Polyphen

0.10

B;.

Vest4

0.069

MVP

0.87

MPC

0.19

ClinPred

0.014

GERP RS

3.8

Varity_R

0.16

gMVP

0.38

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

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