rs1555242247

Positions:

• chr11-68906182-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_002180.3(IGHMBP2):​c.200T>C​(p.Phe67Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: IGHMBP2 NM_002180.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.91

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.972

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IGHMBP2	NM_002180.3	c.200T>C	p.Phe67Ser	missense_variant	2/15	ENST00000255078.8	NP_002171.2
IGHMBP2	XM_047426881.1	c.200T>C	p.Phe67Ser	missense_variant	2/15		XP_047282837.1
IGHMBP2	XM_017017671.3	c.200T>C	p.Phe67Ser	missense_variant	2/12		XP_016873160.1
IGHMBP2	XM_005273976.3	c.200T>C	p.Phe67Ser	missense_variant	2/9		XP_005274033.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IGHMBP2	ENST00000255078.8	c.200T>C	p.Phe67Ser	missense_variant	2/15	1	NM_002180.3	ENSP00000255078.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

Uncertain significance, criteria provided, single submitter

case-control

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

Jan 21, 2018

Missense mutation in the DNA helicase domain (region 1B). Poorly conserved across species. Never published yet. Presented a sudden respiratory distress at 6 months old requiring mechanical ventilation, 2 months after discovering a right phrenic palsy, tracheostomized at 18 months old. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.67	D;.
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.84	T;T
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Uncertain	0.74	D
MutationAssessor	Uncertain	2.4	M;.
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-3.7	D;D
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0070	D;D
Polyphen		0.73	P;.
Vest4		0.80
MutPred		0.88		Gain of disorder (P = 0.0021);Gain of disorder (P = 0.0021);
MVP		0.97
MPC		0.85
ClinPred		0.99	D
GERP RS		3.6
Varity_R		0.77
gMVP		0.82

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1555242247; hg19: chr11-68673650;