rs137852670

Positions:

• chr11-68929229-C-G
• chr11-68929229-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The ENST00000255078.8(IGHMBP2):​c.1107C>G​(p.Phe369Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F369Y) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: IGHMBP2 ENST00000255078.8 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.320

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 6 uncertain in ENST00000255078.8
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988
• PP5: Variant 11-68929229-C-G is Pathogenic according to our data. Variant chr11-68929229-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 9119.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr11-68929229-C-G is described in Lovd as [Pathogenic]. Variant chr11-68929229-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IGHMBP2	NM_002180.3	c.1107C>G	p.Phe369Leu	missense_variant	8/15	ENST00000255078.8	NP_002171.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IGHMBP2	ENST00000255078.8	c.1107C>G	p.Phe369Leu	missense_variant	8/15	1	NM_002180.3	ENSP00000255078	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Autosomal recessive distal spinal muscular atrophy 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 17, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.78	D
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.69
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.52	D
MutationAssessor	Uncertain	2.8	M
MutationTaster	Benign	1.0	A
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-5.4	D
REVEL	Pathogenic	0.68
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.0070	D
Polyphen		1.0	D
Vest4		0.88
MutPred		0.89		Loss of stability (P = 0.0266);
MVP		0.90
MPC		0.81
ClinPred		1.0	D
GERP RS		-9.0
Varity_R		0.91
gMVP		0.87

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: rs137852670; hg19: chr11-68696697;