11-68903809-A-G

Variant names:

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PVS1_SupportingBP6_Very_StrongBA1

The NM_181514.2(MRPL21):c.2T>C(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00386 in 1,204,898 control chromosomes in the GnomAD database, including 101 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.023 ( 54 hom., cov: 31)

Exomes 𝑓: 0.0021 ( 47 hom. )

Consequence

MRPL21
NM_181514.2 start_lost

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.501

Variant links:

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]

MRPL21 links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -15 ACMG points.

PVS1

Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 86 codons. Genomic position: 68896655. Lost 0.414 part of the original CDS.

BP6

Variant 11-68903809-A-G is Benign according to our data. Variant chr11-68903809-A-G is described in ClinVar as [Benign]. Clinvar id is 1264772.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0782 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MRPL21	NM_181514.2 link	c.2T>C	p.Met1?	start_lost	Exon 1 of 7	ENST00000362034.7	NP_852615.1	Q7Z2W9-1
IGHMBP2	NM_002180.3 link	c.-144A>G		upstream_gene_variant		ENST00000255078.8	NP_002171.2	P38935

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MRPL21	ENST00000362034.7 link	c.2T>C	p.Met1?	start_lost	Exon 1 of 7	1	NM_181514.2	ENSP00000354580.2		Q7Z2W9-1
IGHMBP2	ENST00000255078.8 link	c.-144A>G		upstream_gene_variant		1	NM_002180.3	ENSP00000255078.4		P38935

Frequencies

GnomAD3 genomes

AF:

0.0225

AC:

2286

AN:

101564

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0807

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00661

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000434

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000261

Gnomad OTH

AF:

0.0142

GnomAD3 exomes

AF:

0.00540

AC:

941

AN:

174254

Hom.:

AF XY:

0.00421

AC XY:

390

AN XY:

92692

show subpopulations

Gnomad AFR exome

AF:

0.0728

Gnomad AMR exome

AF:

0.00276

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000215

Gnomad OTH exome

AF:

0.00252

GnomAD4 exome

AF:

0.00212

AC:

2342

AN:

1103228

Hom.:

Cov.:

AF XY:

0.00171

AC XY:

947

AN XY:

553316

show subpopulations

Gnomad4 AFR exome

AF:

0.0740

Gnomad4 AMR exome

AF:

0.00295

Gnomad4 ASJ exome

AF:

0.0000504

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000166

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000147

Gnomad4 OTH exome

AF:

0.00416

GnomAD4 genome

AF:

0.0227

AC:

2303

AN:

101670

Hom.:

Cov.:

AF XY:

0.0228

AC XY:

1119

AN XY:

49118

show subpopulations

Gnomad4 AFR

AF:

0.0811

Gnomad4 AMR

AF:

0.00660

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000434

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000261

Gnomad4 OTH

AF:

0.0140

Alfa

AF:

0.00148

Hom.:

Bravo

AF:

0.0168

ExAC

AF:

0.00455

AC:

550

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 08, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.58

CADD

Benign

5.7

DANN

Benign

0.63

DEOGEN2

Benign

0.0031

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.0041

LIST_S2

Uncertain

0.90

MetaRNN

Benign

0.0028

MetaSVM

Benign

-1.1

PROVEAN

Benign

-0.87

REVEL

Benign

0.094

Sift

Benign

0.032

Sift4G

Uncertain

0.032

Polyphen

0.0040

Vest4

0.14

MVP

0.15

ClinPred

0.0014

GERP RS

-0.25

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.36

gMVP

0.32

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over