11-68903959-T-C

Variant names:

• chr11-68903959-T-C
• rs751910797
• NM_002180.3:c.7T>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_002180.3(IGHMBP2):​c.7T>C​(p.Ser3Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000708 in 1,412,122 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S3A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 35)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: IGHMBP2 NM_002180.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.254
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27061135).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002180.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IGHMBP2	NM_002180.3	MANE Select	c.7T>C	p.Ser3Pro	missense	Exon 1 of 15	NP_002171.2	P38935
	MRPL21	NM_181514.2	MANE Select	c.-149A>G		upstream_gene	N/A	NP_852615.1	Q7Z2W9-1
	MRPL21	NM_181515.2		c.-417A>G		upstream_gene	N/A	NP_852616.1	Q7Z2W9-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IGHMBP2	ENST00000255078.8	TSL:1 MANE Select	c.7T>C	p.Ser3Pro	missense	Exon 1 of 15	ENSP00000255078.4	P38935
	IGHMBP2	ENST00000925063.1		c.7T>C	p.Ser3Pro	missense	Exon 1 of 14	ENSP00000595122.1
	IGHMBP2	ENST00000675615.1		c.7T>C	p.Ser3Pro	missense	Exon 1 of 14	ENSP00000502413.1	A0A6Q8PGT6

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD4 exome AF: 7.08e-7 AC: 1 AN: 1412122 Hom.: 0 Cov.: 45 AF XY: 0.00 AC XY: 0 AN XY: 698446

African (AFR) AF: 0.00 AC: 0 AN: 32100

American (AMR) AF: 0.00 AC: 0 AN: 36786

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25298

East Asian (EAS) AF: 0.00 AC: 0 AN: 36724

South Asian (SAS) AF: 0.00 AC: 0 AN: 81648

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48910

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5690

European-Non Finnish (NFE) AF: 9.20e-7 AC: 1 AN: 1086474

Other (OTH) AF: 0.00 AC: 0 AN: 58492

GnomAD4 genome Cov.: 35

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.088	T
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.033	N
LIST_S2	Benign	0.63	T
M_CAP	Pathogenic	0.55	D
MetaRNN	Benign	0.27	T
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.25
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-0.86	N
REVEL	Uncertain	0.33
Sift	Uncertain	0.018	D
Sift4G	Benign	0.35	T
Polyphen		0.47	P
Vest4		0.37
MutPred		0.22		Loss of phosphorylation at S3 (P = 0.0243)
MVP		0.93
MPC		0.47
ClinPred		0.49	T
GERP RS		2.9
PromoterAI		-0.083	Neutral
Varity_R		0.46
gMVP		0.37
Mutation Taster		=93/7	polymorphism

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

Other links and lift over

dbSNP: rs751910797; hg19: chr11-68671427;