11-68903636-A-G

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MRPL21	NM_181514.2	c.88+87T>C		intron_variant	Intron 1 of 6	ENST00000362034.7	NP_852615.1
MRPL21	NM_181515.2	c.-181+87T>C		intron_variant	Intron 1 of 6		NP_852616.1
MRPL21	XM_005273823.5	c.88+87T>C		intron_variant	Intron 1 of 5		XP_005273880.1
MRPL21	XR_247190.5	n.110+87T>C		intron_variant	Intron 1 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MRPL21	ENST00000362034.7	c.88+87T>C		intron_variant	Intron 1 of 6	1	NM_181514.2	ENSP00000354580.2

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

Gnomad4 AFR exome AF: 0.182

Gnomad4 AMR exome AF: 0.132

Gnomad4 ASJ exome AF: 0.359

Gnomad4 EAS exome AF: 0.244

Gnomad4 SAS exome AF: 0.484

Gnomad4 FIN exome AF: 0.375

Gnomad4 NFE exome AF: 0.304

Gnomad4 OTH exome AF: 0.302

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

Gnomad4 AFR AF: 0.182

Gnomad4 AMR AF: 0.179

Gnomad4 ASJ AF: 0.370

Gnomad4 EAS AF: 0.210

Gnomad4 SAS AF: 0.478

Gnomad4 FIN AF: 0.366

Gnomad4 NFE AF: 0.300

Gnomad4 OTH AF: 0.243

Alfa AF: 0.296 Hom.: 10924

Bravo AF: 0.240

Asia WGS AF: 0.327 AC: 1133 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 19, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	8.9
DANN	Benign	0.83

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