1-92836186-A-G

Position:

chr1-92836186-A-G

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP3BP6_Very_StrongBS1BS2

The NM_000969.5(RPL5):c.325-4A>G 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 0.000509 in 1,611,660 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0025 ( 2 hom., cov: 32)

Exomes 𝑓: 0.00030 ( 2 hom. )

Consequence

RPL5
NM_000969.5 splice_region, splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.9934

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.841

Variant links:

Genes affected

RPL5 (HGNC:10360): (ribosomal protein L5) Ribosomes, the organelles that catalyze protein synthesis, consist of a small 40S subunit and a large 60S subunit. Together these subunits are composed of four RNA species and approximately 80 structurally distinct proteins. This gene encodes a member of the L18P family of ribosomal proteins and component of the 60S subunit. The encoded protein binds 5S rRNA to form a stable complex called the 5S ribonucleoprotein particle (RNP), which is necessary for the transport of nonribosome-associated cytoplasmic 5S rRNA to the nucleolus for assembly into ribosomes. The encoded protein may also function to inhibit tumorigenesis through the activation of downstream tumor suppressors and the downregulation of oncoprotein expression. Mutations in this gene have been identified in patients with Diamond-Blackfan Anemia (DBA). This gene is co-transcribed with the small nucleolar RNA gene U21, which is located in its fifth intron. As is typical for genes encoding ribosomal proteins, there are multiple processed pseudogenes of this gene dispersed throughout the genome. [provided by RefSeq, Mar 2017]

RPL5 links:

DIPK1A (HGNC:32213): (divergent protein kinase domain 1A) This gene encodes a member of the FAM69 family of cysteine-rich type II transmembrane proteins. These proteins localize to the endoplasmic reticulum but their specific functions are unknown. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Nov 2011]

DIPK1A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -15 ACMG points.

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

BP6

Variant 1-92836186-A-G is Benign according to our data. Variant chr1-92836186-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 238198.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00248 (377/152288) while in subpopulation AFR AF= 0.00799 (332/41570). AF 95% confidence interval is 0.00728. There are 2 homozygotes in gnomad4. There are 169 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 377 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE
RPL5	NM_000969.5 linkuse as main transcript	c.325-4A>G	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant	ENST00000370321.8
DIPK1A	NM_001252273.2 linkuse as main transcript	c.475-3152T>C	intron_variant
RPL5	NR_146333.1 linkuse as main transcript	n.421-41A>G	intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RPL5	ENST00000370321.8 linkuse as main transcript	c.325-4A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_000969.5	P1

Frequencies

GnomAD3 genomes

AF:

0.00248

AC:

377

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00801

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00210

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00383

GnomAD3 exomes

AF:

0.000701

AC:

176

AN:

251136

Hom.:

AF XY:

0.000449

AC XY:

AN XY:

135738

show subpopulations

Gnomad AFR exome

AF:

0.00830

Gnomad AMR exome

AF:

0.000752

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000882

Gnomad OTH exome

AF:

0.000816

GnomAD4 exome

AF:

0.000304

AC:

444

AN:

1459372

Hom.:

Cov.:

AF XY:

0.000260

AC XY:

189

AN XY:

726030

show subpopulations

Gnomad4 AFR exome

AF:

0.00806

Gnomad4 AMR exome

AF:

0.000895

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000819

Gnomad4 OTH exome

AF:

0.000681

GnomAD4 genome

AF:

0.00248

AC:

377

AN:

152288

Hom.:

Cov.:

AF XY:

0.00227

AC XY:

169

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.00799

Gnomad4 AMR

AF:

0.00209

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00379

Alfa

AF:

0.00136

Hom.:

Bravo

AF:

0.00292

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Oct 29, 2020

DNA sequence analysis of the RPL5 gene demonstrated a sequence change in intron 4, c.325-4A>G. This sequence change has been described in the gnomAD database with a frequency of 0.83% in African populations (dbSNP rs183825489). The c.325-4A>G change has been identified in one individual with Diamond-Blackfan anemia (PMID: 29044489). This sequence change is predicted to have a deleterious effect on splicing based on in silico splice prediction programs. The functional significance of this sequence change is not known at present and its contribution to this patient's disease phenotype cannot definitively be determined. -

Diamond-Blackfan anemia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 19, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

DANN

Benign

0.74

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.99

dbscSNV1_RF

Pathogenic

0.95

SpliceAI score (max)

0.19

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over