11-68903959-T-G

Position:

chr11-68903959-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_002180.3(IGHMBP2):c.7T>G(p.Ser3Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000109 in 1,564,308 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 35)

Exomes 𝑓: 0.0000064 ( 0 hom. )

Consequence

IGHMBP2
NM_002180.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.254

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 Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.10279569).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IGHMBP2	NM_002180.3 linkuse as main transcript	c.7T>G	p.Ser3Ala	missense_variant	1/15	ENST00000255078.8	NP_002171.2	P38935
IGHMBP2	XM_047426881.1 linkuse as main transcript	c.7T>G	p.Ser3Ala	missense_variant	1/15		XP_047282837.1
IGHMBP2	XM_017017671.3 linkuse as main transcript	c.7T>G	p.Ser3Ala	missense_variant	1/12		XP_016873160.1
IGHMBP2	XM_005273976.3 linkuse as main transcript	c.7T>G	p.Ser3Ala	missense_variant	1/9		XP_005274033.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IGHMBP2	ENST00000255078.8 linkuse as main transcript	c.7T>G	p.Ser3Ala	missense_variant	1/15	1	NM_002180.3	ENSP00000255078.4		P38935

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

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

GnomAD3 exomes

AF:

0.0000118

AC:

AN:

169302

Hom.:

AF XY:

0.00

AC XY:

AN XY:

90978

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000780

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000637

AC:

AN:

1412122

Hom.:

Cov.:

AF XY:

0.00000430

AC XY:

AN XY:

698446

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000136

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:

0.00000184

Gnomad4 OTH exome

AF:

0.0000342

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152186

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74346

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000458

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000982

ExAC

AF:

0.0000180

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 31, 2022

This sequence change replaces serine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 3 of the IGHMBP2 protein (p.Ser3Ala). This variant is present in population databases (rs751910797, gnomAD 0.008%). This variant has not been reported in the literature in individuals affected with IGHMBP2-related conditions. ClinVar contains an entry for this variant (Variation ID: 569975). 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 not expected to disrupt IGHMBP2 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.057

BayesDel_addAF

Benign

-0.042

BayesDel_noAF

Benign

-0.11

CADD

Benign

DANN

Benign

0.85

DEOGEN2

Benign

0.078

T;.

Eigen

Benign

-0.74

Eigen_PC

Benign

-0.64

FATHMM_MKL

Benign

0.018

LIST_S2

Benign

0.50

T;T

M_CAP

Uncertain

0.23

MetaRNN

Benign

0.10

T;T

MetaSVM

Benign

-0.68

MutationAssessor

Benign

0.20

N;.

MutationTaster

Benign

0.98

N;N

PrimateAI

Uncertain

0.70

PROVEAN

Benign

-0.49

N;N

REVEL

Benign

0.16

Sift

Benign

0.15

T;T

Sift4G

Benign

0.86

T;T

Polyphen

0.0010

B;.

Vest4

0.22

MutPred

0.22

Loss of phosphorylation at S3 (P = 0.0243);Loss of phosphorylation at S3 (P = 0.0243);

MVP

0.86

MPC

0.16

ClinPred

0.073

GERP RS

2.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.17

gMVP

0.20

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