19-10259609-G-C

Position:

• chr19-10259609-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_015956.3(MRPL4):​c.740-8G>C variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.32 (0 hom., cov: 0)
  • Exomes 𝑓: 0.088 (105 hom.)
  • Failed GnomAD Quality Control
• Consequence: MRPL4 NM_015956.3 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00001430
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• 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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 19-10259609-G-C is Benign according to our data. Variant chr19-10259609-G-C is described in ClinVar as [Benign]. Clinvar id is 403107.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MRPL4	NM_015956.3	c.740-8G>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000253099.11
MRPL4	NM_001411149.1	c.*103G>C		3_prime_UTR_variant	9/9
MRPL4	NM_146388.2	c.*871G>C		3_prime_UTR_variant	8/8
MRPL4	NM_146387.2	c.740-8G>C		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>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_015956.3	P1
	ENST00000587088.1	n.222+215C>G		intron_variant, non_coding_transcript_variant		2
LIMASI	ENST00000592893.1	n.358+603C>G		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00 AC: 7493 AN: 23160 Hom.: 0 Cov.: 0 FAILED QC

Gnomad AFR AF: 0.296

Gnomad AMI AF: 0.400

Gnomad AMR AF: 0.156

Gnomad ASJ AF: 0.431

Gnomad EAS AF: 0.282

Gnomad SAS AF: 0.338

Gnomad FIN AF: 0.179

Gnomad MID AF: 0.0938

Gnomad NFE AF: 0.426

Gnomad OTH AF: 0.313

GnomAD3 exomes AF: 0.314 AC: 21608 AN: 68894 Hom.: 6 AF XY: 0.309 AC XY: 11689 AN XY: 37844

Gnomad AFR exome AF: 0.243

Gnomad AMR exome AF: 0.377

Gnomad ASJ exome AF: 0.437

Gnomad EAS exome AF: 0.326

Gnomad SAS exome AF: 0.410

Gnomad FIN exome AF: 0.345

Gnomad NFE exome AF: 0.252

Gnomad OTH exome AF: 0.373

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0875 AC: 33862 AN: 386818 Hom.: 105 Cov.: 34 AF XY: 0.0969 AC XY: 18183 AN XY: 187656

Gnomad4 AFR exome AF: 0.139

Gnomad4 AMR exome AF: 0.365

Gnomad4 ASJ exome AF: 0.253

Gnomad4 EAS exome AF: 0.170

Gnomad4 SAS exome AF: 0.290

Gnomad4 FIN exome AF: 0.280

Gnomad4 NFE exome AF: 0.0518

Gnomad4 OTH exome AF: 0.111

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR;InbreedingCoeff AF: 0.323 AC: 7493 AN: 23176 Hom.: 0 Cov.: 0 AF XY: 0.290 AC XY: 3396 AN XY: 11728

Gnomad4 AFR AF: 0.295

Gnomad4 AMR AF: 0.156

Gnomad4 ASJ AF: 0.431

Gnomad4 EAS AF: 0.281

Gnomad4 SAS AF: 0.338

Gnomad4 FIN AF: 0.179

Gnomad4 NFE AF: 0.426

Gnomad4 OTH AF: 0.311

Alfa AF: 0.00249 Hom.: 0

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 29, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.45
DANN	Benign	0.50

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000014
dbscSNV1_RF	Benign	0.0040

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;