rs113792800

chr1-92834847-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000969.5(RPL5):c.258T>C(p.Tyr86=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00251 in 1,609,238 control chromosomes in the GnomAD database, including 63 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0054 (11 hom., cov: 32)
  • Exomes 𝑓: 0.0022 (52 hom.)
• Consequence: RPL5 NM_000969.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -3.47

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]

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 1-92834847-T-C is Benign according to our data. Variant chr1-92834847-T-C is described in ClinVar as [Benign]. Clinvar id is 238197.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.47 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00537 (818/152316) while in subpopulation SAS AF= 0.0282 (136/4826). AF 95% confidence interval is 0.0243. There are 11 homozygotes in gnomad4. There are 424 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 812 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RPL5	NM_000969.5	c.258T>C	p.Tyr86=	synonymous_variant	4/8	ENST00000370321.8
DIPK1A	NM_001252273.2	c.475-1813A>G		intron_variant
RPL5	NR_146333.1	n.387T>C		non_coding_transcript_exon_variant	4/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RPL5	ENST00000370321.8	c.258T>C	p.Tyr86=	synonymous_variant	4/8	1	NM_000969.5	P1

Frequencies

GnomAD3 genomes AF: 0.00534 AC: 812 AN: 152198 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.0148

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00192

Gnomad SAS AF: 0.0288

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00482 AC: 1189 AN: 246684 Hom.: 15 AF XY: 0.00550 AC XY: 736 AN XY: 133800

Gnomad AFR exome AF: 0.0156

Gnomad AMR exome AF: 0.000954

Gnomad ASJ exome AF: 0.00189

Gnomad EAS exome AF: 0.00365

Gnomad SAS exome AF: 0.0246

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000388

Gnomad OTH exome AF: 0.00311

GnomAD4 exome AF: 0.00221 AC: 3215 AN: 1456922 Hom.: 52 Cov.: 31 AF XY: 0.00286 AC XY: 2071 AN XY: 725042

Gnomad4 AFR exome AF: 0.0165

Gnomad4 AMR exome AF: 0.00103

Gnomad4 ASJ exome AF: 0.00218

Gnomad4 EAS exome AF: 0.00186

Gnomad4 SAS exome AF: 0.0235

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000221

Gnomad4 OTH exome AF: 0.00341

GnomAD4 genome AF: 0.00537 AC: 818 AN: 152316 Hom.: 11 Cov.: 32 AF XY: 0.00569 AC XY: 424 AN XY: 74494

Gnomad4 AFR AF: 0.0150

Gnomad4 AMR AF: 0.00163

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00193

Gnomad4 SAS AF: 0.0282

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00299 Hom.: 1

Bravo AF: 0.00542

Asia WGS AF: 0.0180 AC: 63 AN: 3478

EpiCase AF: 0.000491

EpiControl AF: 0.000474

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Diamond-Blackfan anemia Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	May 10, 2016	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 16, 2015

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Diamond-Blackfan anemia 6 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	0.075
Dann	Benign	0.49
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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

Other links and lift over

dbSNP: rs113792800; hg19: chr1-93300404;