rs375741179

chr19-10259609-G-Achr19-10259609-G-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_015956.3(MRPL4):c.740-8G>A variant causes a splice region, splice polypyrimidine tract, 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, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0001782
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.31

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]

(HGNC:):

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

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MRPL4	NM_015956.3	c.740-8G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000253099.11
MRPL4	NM_001411149.1	c.*103G>A		3_prime_UTR_variant	9/9
MRPL4	NM_146388.2	c.*871G>A		3_prime_UTR_variant	8/8
MRPL4	NM_146387.2	c.740-8G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MRPL4	ENST00000253099.11	c.740-8G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_015956.3	P1
	ENST00000587088.1	n.222+215C>T		intron_variant, non_coding_transcript_variant		2
LIMASI	ENST00000592893.1	n.358+603C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.000252 AC: 7 AN: 27768 Hom.: 0 Cov.: 0

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

GnomAD3 exomes AF: 0.000174 AC: 12 AN: 68894 Hom.: 0 AF XY: 0.000211 AC XY: 8 AN XY: 37844

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000328

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000231 AC: 92 AN: 398294 Hom.: 0 Cov.: 34 AF XY: 0.000277 AC XY: 54 AN XY: 194728

Gnomad4 AFR exome AF: 0.000105

Gnomad4 AMR exome AF: 0.0000812

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00105

Gnomad4 SAS exome AF: 0.000134

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000240

Gnomad4 OTH exome AF: 0.000207

GnomAD4 genome AF: 0.000252 AC: 7 AN: 27790 Hom.: 0 Cov.: 0 AF XY: 0.000424 AC XY: 6 AN XY: 14156

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00833

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000179

Gnomad4 OTH AF: 0.00236

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	1.1
Dann	Benign	0.56

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

LitVar

Other links and lift over

dbSNP: rs375741179; hg19: chr19-10370285;