rs629426

Variant names:

• chr11-68903636-A-G
• rs629426
• NM_181514.2:c.88+87T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_181514.2(MRPL21):​c.88+87T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.304 in 1,360,118 control chromosomes in the GnomAD database, including 66,725 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (5788 hom., cov: 34)
  • Exomes 𝑓: 0.31 (60937 hom.)
• Consequence: MRPL21 NM_181514.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.559
• Publications: 34 publications found

Genes affected

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]

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 Gene-Disease associations (from GenCC):

• autosomal recessive distal spinal muscular atrophy 1

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Ambry Genetics, Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)
• Charcot-Marie-Tooth disease axonal type 2S

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Laboratory for Molecular Medicine, Orphanet, Labcorp Genetics (formerly Invitae)
• hereditary peripheral neuropathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 11-68903636-A-G is Benign according to our data. Variant chr11-68903636-A-G is described in ClinVar as Benign. ClinVar VariationId is 668907.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.462 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_181514.2. 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
	MRPL21	NM_181514.2	MANE Select	c.88+87T>C		intron	N/A	NP_852615.1	Q7Z2W9-1
	MRPL21	NM_181515.2		c.-181+87T>C		intron	N/A	NP_852616.1	Q7Z2W9-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MRPL21	ENST00000362034.7	TSL:1 MANE Select	c.88+87T>C		intron	N/A	ENSP00000354580.2	Q7Z2W9-1
	MRPL21	ENST00000567045.5	TSL:2	c.-181+87T>C		intron	N/A	ENSP00000457859.1	H3BUY0
	MRPL21	ENST00000918368.1		c.88+87T>C		intron	N/A	ENSP00000588427.1

Frequencies

GnomAD3 genomes AF: 0.263 AC: 40042 AN: 152140 Hom.: 5791 Cov.: 34

Gnomad AFR AF: 0.182

Gnomad AMI AF: 0.153

Gnomad AMR AF: 0.179

Gnomad ASJ AF: 0.370

Gnomad EAS AF: 0.210

Gnomad SAS AF: 0.478

Gnomad FIN AF: 0.366

Gnomad MID AF: 0.360

Gnomad NFE AF: 0.300

Gnomad OTH AF: 0.245

GnomAD4 exome AF: 0.309 AC: 373483 AN: 1207858 Hom.: 60937 AF XY: 0.317 AC XY: 193084 AN XY: 608698

African (AFR) AF: 0.182 AC: 5189 AN: 28478

American (AMR) AF: 0.132 AC: 5574 AN: 42226

Ashkenazi Jewish (ASJ) AF: 0.359 AC: 8492 AN: 23668

East Asian (EAS) AF: 0.244 AC: 9324 AN: 38186

South Asian (SAS) AF: 0.484 AC: 39164 AN: 80894

European-Finnish (FIN) AF: 0.375 AC: 18884 AN: 50380

Middle Eastern (MID) AF: 0.350 AC: 1706 AN: 4868

European-Non Finnish (NFE) AF: 0.304 AC: 269530 AN: 887402

Other (OTH) AF: 0.302 AC: 15620 AN: 51756

GnomAD4 genome AF: 0.263 AC: 40053 AN: 152260 Hom.: 5788 Cov.: 34 AF XY: 0.268 AC XY: 19976 AN XY: 74440

African (AFR) AF: 0.182 AC: 7565 AN: 41558

American (AMR) AF: 0.179 AC: 2738 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.370 AC: 1283 AN: 3470

East Asian (EAS) AF: 0.210 AC: 1086 AN: 5168

South Asian (SAS) AF: 0.478 AC: 2310 AN: 4830

European-Finnish (FIN) AF: 0.366 AC: 3875 AN: 10598

Middle Eastern (MID) AF: 0.371 AC: 109 AN: 294

European-Non Finnish (NFE) AF: 0.300 AC: 20434 AN: 68014

Other (OTH) AF: 0.243 AC: 514 AN: 2114

Alfa AF: 0.286 Hom.: 17725

Bravo AF: 0.240

Asia WGS AF: 0.327 AC: 1133 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	8.9
DANN	Benign	0.83
PhyloP100		-0.56
PromoterAI		0.059	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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: rs629426; hg19: chr11-68671104; COSMIC: COSV54821997; COSMIC: COSV54821997;