Genetic Variant MRPL4:c.740-8G>A (chr19-10259609-G-A) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_015956.3(MRPL4):c.740-8G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000232 in 426,084 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.00025 ( 0 hom., cov: 0)

Exomes 𝑓: 0.00023 ( 0 hom. )

Consequence

MRPL4
NM_015956.3 splice_region, intron

Scores

Splicing: ADA: 0.0001782

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.31

Publications

0 publications found

Variant links:

Genes affected

MRPL4 (HGNC:14276): (mitochondrial ribosomal protein L4) 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. Sequence analysis identified alternatively spliced variants that encode different protein isoforms. [provided by RefSeq, Jul 2008]

MRPL4 links:

LIMASI (HGNC:56357): (lncRNA inflammatory and mucous response associated, antisense to ICAM1)

LIMASI links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015956.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
MRPL4	NM_015956.3	MANE Select	c.740-8G>A	splice_region intron	N/A	NP_057040.2
MRPL4	NM_001411149.1		c.*103G>A	3_prime_UTR	Exon 9 of 9	NP_001398078.1
MRPL4	NM_146388.2		c.*871G>A	3_prime_UTR	Exon 8 of 8	NP_666500.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
MRPL4	ENST00000253099.11	TSL:1 MANE Select	c.740-8G>A	splice_region intron	N/A	ENSP00000253099.5
MRPL4	ENST00000393733.6	TSL:5	c.*103G>A	3_prime_UTR	Exon 9 of 9	ENSP00000377334.2
MRPL4	ENST00000930030.1		c.914-8G>A	splice_region intron	N/A	ENSP00000600089.1

Frequencies

GnomAD3 genomes

AF:

0.000252

AC:

AN:

27768

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00837

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000179

Gnomad OTH

AF:

0.00237

GnomAD2 exomes

AF:

0.000174

AC:

AN:

68894

AF XY:

0.000211

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000371

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000328

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000231

AC:

AN:

398294

Hom.:

Cov.:

AF XY:

0.000277

AC XY:

AN XY:

194728

show subpopulations

African (AFR)

AF:

0.000105

AC:

AN:

9552

American (AMR)

AF:

0.0000812

AC:

AN:

12322

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

5156

East Asian (EAS)

AF:

0.00105

AC:

AN:

7596

South Asian (SAS)

AF:

0.000134

AC:

AN:

22350

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8440

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1036

European-Non Finnish (NFE)

AF:

0.000240

AC:

AN:

317322

Other (OTH)

AF:

0.000207

AC:

AN:

14520

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

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

AF:

0.000252

AC:

AN:

27790

Hom.:

Cov.:

AF XY:

0.000424

AC XY:

AN XY:

14156

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

7784

American (AMR)

AF:

0.00

AC:

AN:

4398

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

550

East Asian (EAS)

AF:

0.00833

AC:

AN:

480

South Asian (SAS)

AF:

0.00

AC:

AN:

484

European-Finnish (FIN)

AF:

0.00

AC:

AN:

2358

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.000179

AC:

AN:

11188

Other (OTH)

AF:

0.00236

AC:

AN:

424

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

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:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

1.1

(source)

DANN

Benign

0.56

PhyloP100

-1.3

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00018

dbscSNV1_RF

Benign

0.074

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