Genetic Variant MRPL4:c.740-13A>G (chr19-10259604-A-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001411149.1(MRPL4):c.*98A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000228 in 351,558 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000067 ( 0 hom., cov: 0)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

MRPL4
NM_001411149.1 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.623

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 -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.77).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001411149.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
MRPL4	NM_015956.3	MANE Select	c.740-13A>G	intron	N/A	NP_057040.2
MRPL4	NM_001411149.1		c.*98A>G	3_prime_UTR	Exon 9 of 9	NP_001398078.1	X6RAY8
MRPL4	NM_146388.2		c.*866A>G	3_prime_UTR	Exon 8 of 8	NP_666500.1	Q9BYD3-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
MRPL4	ENST00000253099.11	TSL:1 MANE Select	c.740-13A>G	intron	N/A	ENSP00000253099.5	Q9BYD3-1
MRPL4	ENST00000393733.6	TSL:5	c.*98A>G	3_prime_UTR	Exon 9 of 9	ENSP00000377334.2	X6RAY8
MRPL4	ENST00000930030.1		c.914-13A>G	intron	N/A	ENSP00000600089.1

Frequencies

GnomAD3 genomes

AF:

0.0000675

AC:

AN:

29616

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:

0.00200

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000824

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000186

AC:

AN:

321912

Hom.:

Cov.:

AF XY:

0.0000317

AC XY:

AN XY:

157762

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

8110

American (AMR)

AF:

0.00

AC:

AN:

10564

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

4886

East Asian (EAS)

AF:

0.00

AC:

AN:

6650

South Asian (SAS)

AF:

0.0000468

AC:

AN:

21356

European-Finnish (FIN)

AF:

0.00

AC:

AN:

7680

Middle Eastern (MID)

AF:

0.00

AC:

AN:

784

European-Non Finnish (NFE)

AF:

0.0000200

AC:

AN:

249918

Other (OTH)

AF:

0.00

AC:

AN:

11964

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.433

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:

0.0000675

AC:

AN:

29646

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

14992

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:

8274

American (AMR)

AF:

0.00

AC:

AN:

4572

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

606

East Asian (EAS)

AF:

0.00198

AC:

AN:

504

South Asian (SAS)

AF:

0.00

AC:

AN:

550

European-Finnish (FIN)

AF:

0.00

AC:

AN:

2444

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0000824

AC:

AN:

12130

Other (OTH)

AF:

0.00

AC:

AN:

448

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0296732), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.400

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.77

CADD

Benign

3.3

(source)

DANN

Benign

0.67

PhyloP100

-0.62

Splicing

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over