rs11540832

Variant names:

• chr1-92837557-A-G
• rs11540832
• NM_000969.5:c.629A>G

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_000969.5(RPL5):​c.629A>G​(p.Tyr210Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00733 in 1,612,022 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0055 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0075 (42 hom.)
• Consequence: RPL5 NM_000969.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 3.70
• Publications: 11 publications found

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]

SNORD21 (HGNC:10144): (small nucleolar RNA, C/D box 21) This gene encodes a small nucleolar RNA (snoRNA) that may be involved in biogenesis of the large (28S) ribosomal subunit. This gene is found within an intron of the RPL5 gene. [provided by RefSeq, Mar 2009]

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009437233).
• BP6: Variant 1-92837557-A-G is Benign according to our data. Variant chr1-92837557-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 238200.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 838 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000969.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPL5	NM_000969.5	MANE Select	c.629A>G	p.Tyr210Cys	missense	Exon 6 of 8	NP_000960.2
	DIPK1A	NM_001252273.2		c.475-4523T>C		intron	N/A	NP_001239202.1	Q5T7M9-2
	RPL5	NR_146333.1		n.688A>G		non_coding_transcript_exon	Exon 6 of 8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPL5	ENST00000370321.8	TSL:1 MANE Select	c.629A>G	p.Tyr210Cys	missense	Exon 6 of 8	ENSP00000359345.2	P46777
	DIPK1A	ENST00000615519.4	TSL:1	c.475-4523T>C		intron	N/A	ENSP00000483279.1	Q5T7M9-2
	RPL5	ENST00000880515.1		c.629A>G	p.Tyr210Cys	missense	Exon 6 of 8	ENSP00000550574.1

Frequencies

GnomAD3 genomes AF: 0.00551 AC: 838 AN: 152204 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.00150

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00275

Gnomad ASJ AF: 0.00692

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00433

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00964

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00470 AC: 1179 AN: 250596 AF XY: 0.00463

Gnomad AFR exome AF: 0.00149

Gnomad AMR exome AF: 0.00173

Gnomad ASJ exome AF: 0.00417

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00448

Gnomad NFE exome AF: 0.00807

Gnomad OTH exome AF: 0.00376

GnomAD4 exome AF: 0.00752 AC: 10975 AN: 1459700 Hom.: 42 Cov.: 30 AF XY: 0.00727 AC XY: 5279 AN XY: 726158

African (AFR) AF: 0.00108 AC: 36 AN: 33410

American (AMR) AF: 0.00186 AC: 83 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00498 AC: 130 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.000696 AC: 60 AN: 86160

European-Finnish (FIN) AF: 0.00434 AC: 232 AN: 53416

Middle Eastern (MID) AF: 0.00210 AC: 9 AN: 4284

European-Non Finnish (NFE) AF: 0.00905 AC: 10066 AN: 1111690

Other (OTH) AF: 0.00596 AC: 359 AN: 60210

GnomAD4 genome AF: 0.00550 AC: 838 AN: 152322 Hom.: 3 Cov.: 33 AF XY: 0.00497 AC XY: 370 AN XY: 74484

African (AFR) AF: 0.00149 AC: 62 AN: 41578

American (AMR) AF: 0.00275 AC: 42 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00692 AC: 24 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4822

European-Finnish (FIN) AF: 0.00433 AC: 46 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00964 AC: 656 AN: 68034

Other (OTH) AF: 0.00236 AC: 5 AN: 2116

Alfa AF: 0.00652 Hom.: 5

Bravo AF: 0.00538

TwinsUK AF: 0.00971 AC: 36

ALSPAC AF: 0.00856 AC: 33

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00768 AC: 66

ExAC AF: 0.00441 AC: 535

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00736

EpiControl AF: 0.00741

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	Diamond-Blackfan anemia (2)
-	-	2	Diamond-Blackfan anemia 6 (2)
-	-	1	Diamond-Blackfan anemia 1 (1)
-	-	1	not specified (1)
-	-	1	RPL5-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.22	T
Eigen	Benign	0.035
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.0055	T
MetaRNN	Benign	0.0094	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	2.0	M
PhyloP100		3.7
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.14
Sift	Benign	0.17	T
Sift4G	Benign	0.18	T
Polyphen		0.0080	B
Vest4		0.68
MVP		0.58
MPC		1.6
ClinPred		0.018	T
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.45
gMVP		0.54
Mutation Taster		=92/8	polymorphism

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

Other links and lift over

dbSNP: rs11540832; hg19: chr1-93303114; COSMIC: COSV99044227; COSMIC: COSV99044227;