rs771853806

Variant names:

• chr11-68904016-G-T
• rs771853806
• NM_002180.3:c.64G>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_002180.3(IGHMBP2):​c.64G>T​(p.Asp22Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000715 in 1,397,686 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: IGHMBP2 NM_002180.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.48

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]

MRPL21 (HGNC:14479): (mitochondrial ribosomal protein L21) Mammalian mitochondrial ribosomal proteins are encoded by nuclear genes and help in protein synthesis within the mitochondrion. Mitochondrial ribosomes (mitoribosomes) consist of a small 28S subunit and a large 39S subunit. They have an estimated 75% protein to rRNA composition compared to prokaryotic ribosomes, where this ratio is reversed. Another difference between mammalian mitoribosomes and prokaryotic ribosomes is that the latter contain a 5S rRNA. Among different species, the proteins comprising the mitoribosome differ greatly in sequence, and sometimes in biochemical properties, which prevents easy recognition by sequence homology. This gene encodes a 39S subunit protein. Multiple transcript variants encoding different isoforms were identified through sequence analysis although some may be subject to nonsense-mediated decay (NMD). [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGHMBP2	NM_002180.3	c.64G>T	p.Asp22Tyr	missense_variant	Exon 1 of 15	ENST00000255078.8	NP_002171.2
MRPL21	NM_181514.2	c.-206C>A		upstream_gene_variant		ENST00000362034.7	NP_852615.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IGHMBP2	ENST00000255078.8	c.64G>T	p.Asp22Tyr	missense_variant	Exon 1 of 15	1	NM_002180.3	ENSP00000255078.4
MRPL21	ENST00000362034.7	c.-206C>A		upstream_gene_variant		1	NM_181514.2	ENSP00000354580.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.15e-7 AC: 1 AN: 1397686 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 689412

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 9.27e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000149 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Apr 10, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with IGHMBP2-related disease. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This sequence change replaces aspartic acid with tyrosine at codon 22 of the IGHMBP2 protein (p.Asp22Tyr). The aspartic acid residue is weakly conserved and there is a large physicochemical difference between aspartic acid and tyrosine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.43	T;.
Eigen	Uncertain	0.27
Eigen_PC	Benign	0.21
FATHMM_MKL	Benign	0.18	N
LIST_S2	Uncertain	0.89	D;D
M_CAP	Pathogenic	0.61	D
MetaRNN	Uncertain	0.48	T;T
MetaSVM	Uncertain	0.31	D
MutationAssessor	Uncertain	2.1	M;.
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-3.4	D;D
REVEL	Uncertain	0.45
Sift	Uncertain	0.015	D;D
Sift4G	Uncertain	0.0080	D;D
Polyphen		0.89	P;.
Vest4		0.43
MutPred		0.38		Loss of disorder (P = 0.0073);Loss of disorder (P = 0.0073);
MVP		0.95
MPC		0.62
ClinPred		0.97	D
GERP RS		2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.45
gMVP		0.58

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

Other links and lift over

dbSNP: rs771853806; hg19: chr11-68671484; COSMIC: COSV99661906; COSMIC: COSV99661906;