rs200007067
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate
The NM_002180.3(IGHMBP2):c.1108G>A(p.Asp370Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000101 in 1,613,764 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 Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. D370D) has been classified as Likely benign.
Frequency
Consequence
NM_002180.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
IGHMBP2 | NM_002180.3 | c.1108G>A | p.Asp370Asn | missense_variant | 8/15 | ENST00000255078.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
IGHMBP2 | ENST00000255078.8 | c.1108G>A | p.Asp370Asn | missense_variant | 8/15 | 1 | NM_002180.3 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000723 AC: 11AN: 152148Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000187 AC: 47AN: 251112Hom.: 0 AF XY: 0.000162 AC XY: 22AN XY: 135780
GnomAD4 exome AF: 0.000104 AC: 152AN: 1461498Hom.: 0 Cov.: 32 AF XY: 0.0000963 AC XY: 70AN XY: 727082
GnomAD4 genome AF: 0.0000722 AC: 11AN: 152266Hom.: 0 Cov.: 33 AF XY: 0.0000806 AC XY: 6AN XY: 74442
ClinVar
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 | Invitae | Feb 08, 2022 | This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 370 of the IGHMBP2 protein (p.Asp370Asn). This variant is present in population databases (rs200007067, gnomAD 0.03%). 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: 245628). 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. 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. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 15, 2022 | The c.1108G>A (p.D370N) alteration is located in exon 8 (coding exon 8) of the IGHMBP2 gene. This alteration results from a G to A substitution at nucleotide position 1108, causing the aspartic acid (D) at amino acid position 370 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 31, 2020 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at