Genetic Variant MRPL23:c.141-8G>A (chr11-1952119-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBP6_Very_Strong

The NM_021134.4(MRPL23):c.141-8G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.00046 ( 0 hom., cov: 2)

Exomes 𝑓: 0.00028 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

MRPL23
NM_021134.4 splice_region, intron

Scores

Splicing: ADA: 0.00008258

Clinical Significance

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

Conservation

PhyloP100: -0.649

Publications

2 publications found

Variant links:

Genes affected

MRPL23 (HGNC:10322): (mitochondrial ribosomal protein L23) 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. The gene is biallelically expressed, despite its location within a region of imprinted genes on chromosome 11. [provided by RefSeq, Jul 2008]

MRPL23 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BP6

Variant 11-1952119-G-A is Benign according to our data. Variant chr11-1952119-G-A is described in ClinVar as Benign. ClinVar VariationId is 791542.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021134.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
MRPL23	NM_021134.4	MANE Select	c.141-8G>A	splice_region intron	N/A	NP_066957.3
MRPL23	NM_001400176.1		c.141-8G>A	splice_region intron	N/A	NP_001387105.1
MRPL23	NM_001400179.1		c.141-8G>A	splice_region intron	N/A	NP_001387108.1	A8MYK1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
MRPL23	ENST00000397298.8	TSL:1 MANE Select	c.141-8G>A	splice_region intron	N/A	ENSP00000380466.3	Q16540
MRPL23	ENST00000924183.1		c.141-8G>A	splice_region intron	N/A	ENSP00000594242.1
MRPL23	ENST00000397297.7	TSL:2	c.141-8G>A	splice_region intron	N/A	ENSP00000380465.3	A8MYK1

Frequencies

GnomAD3 genomes

AF:

0.000456

AC:

AN:

17540

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.0159

Gnomad AMR

AF:

0.00101

Gnomad ASJ

AF:

0.00181

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000319

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00289

AC:

727

AN:

251328

AF XY:

0.00295

show subpopulations

Gnomad AFR exome

AF:

0.000862

Gnomad AMR exome

AF:

0.00437

Gnomad ASJ exome

AF:

0.0129

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000508

Gnomad NFE exome

AF:

0.00267

Gnomad OTH exome

AF:

0.00767

GnomAD4 exome

AF:

0.000277

AC:

AN:

97538

Hom.:

Cov.:

AF XY:

0.000271

AC XY:

AN XY:

51684

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

1472

American (AMR)

AF:

0.000309

AC:

AN:

3232

Ashkenazi Jewish (ASJ)

AF:

0.00142

AC:

AN:

2818

East Asian (EAS)

AF:

0.00

AC:

AN:

3460

South Asian (SAS)

AF:

0.000222

AC:

AN:

9006

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6710

Middle Eastern (MID)

AF:

0.00701

AC:

AN:

428

European-Non Finnish (NFE)

AF:

0.000215

AC:

AN:

65006

Other (OTH)

AF:

0.000555

AC:

AN:

5406

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.292

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000456

AC:

AN:

17554

Hom.:

Cov.:

AF XY:

0.000258

AC XY:

AN XY:

7746

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

1834

American (AMR)

AF:

0.00101

AC:

AN:

992

Ashkenazi Jewish (ASJ)

AF:

0.00181

AC:

AN:

552

East Asian (EAS)

AF:

0.00

AC:

AN:

346

South Asian (SAS)

AF:

0.00

AC:

AN:

200

European-Finnish (FIN)

AF:

0.00

AC:

AN:

698

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.000319

AC:

AN:

12552

Other (OTH)

AF:

0.00

AC:

AN:

228

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000000000113132), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.306

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00300

Hom.:

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.00382

EpiControl

AF:

0.00397

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

0.24

(source)

DANN

Benign

0.73

PhyloP100

-0.65

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000083

dbscSNV1_RF

Benign

0.014

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over