22-39317633-CA-CAA

Variant names:

• chr22-39317633-C-CA
• rs201453499
• NM_000967.4:c.197-5dupT

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP6_Moderate BS2

The NM_000967.4(RPL3):​c.197-5dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000468 in 1,551,016 control chromosomes in the GnomAD database, including 1 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00038 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00048 (1 hom.)
• Consequence: RPL3 NM_000967.4 splice_region, intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.858
• Publications: 0 publications found

Genes affected

RPL3 (HGNC:10332): (ribosomal protein L3) Ribosomes, the complexes that catalyze protein synthesis, consist of a small 40S subunit and a large 60S subunit. Together these subunits are composed of 4 RNA species and approximately 80 structurally distinct proteins. This gene encodes a ribosomal protein that is a component of the 60S subunit. The protein belongs to the L3P family of ribosomal proteins and it is located in the cytoplasm. The protein can bind to the HIV-1 TAR mRNA, and it has been suggested that the protein contributes to tat-mediated transactivation. This gene is co-transcribed with several small nucleolar RNA genes, which are located in several of this gene's introns. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. As is typical for genes encoding ribosomal proteins, there are multiple processed pseudogenes of this gene dispersed through the genome. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP6: Variant 22-39317633-C-CA is Benign according to our data. Variant chr22-39317633-C-CA is described in ClinVar as Benign. ClinVar VariationId is 781529.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 57 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000967.4. 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
	RPL3	NM_000967.4	MANE Select	c.197-5dupT		splice_region intron	N/A	NP_000958.1	P39023
	RPL3	NM_001033853.2		c.197-5dupT		splice_region intron	N/A	NP_001029025.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPL3	ENST00000216146.9	TSL:1 MANE Select	c.197-5_197-4insT		splice_region intron	N/A	ENSP00000346001.3	P39023
	RPL3	ENST00000401609.5	TSL:1	c.41-5_41-4insT		splice_region intron	N/A	ENSP00000386101.1	G5E9G0
	RPL3	ENST00000465618.5	TSL:1	n.857-5_857-4insT		splice_region intron	N/A

Frequencies

GnomAD3 genomes AF: 0.000379 AC: 57 AN: 150228 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000122

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00172

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000970

Gnomad SAS AF: 0.000844

Gnomad FIN AF: 0.000197

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000178

Gnomad OTH AF: 0.00145

GnomAD2 exomes AF: 0.000750 AC: 151 AN: 201362 AF XY: 0.000769

Gnomad AFR exome AF: 0.000140

Gnomad AMR exome AF: 0.00140

Gnomad ASJ exome AF: 0.000279

Gnomad EAS exome AF: 0.00228

Gnomad FIN exome AF: 0.000156

Gnomad NFE exome AF: 0.000447

Gnomad OTH exome AF: 0.000850

GnomAD4 exome AF: 0.000478 AC: 669 AN: 1400678 Hom.: 1 Cov.: 31 AF XY: 0.000518 AC XY: 361 AN XY: 696620

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000322 AC: 10 AN: 31076

American (AMR) AF: 0.00163 AC: 63 AN: 38602

Ashkenazi Jewish (ASJ) AF: 0.000368 AC: 9 AN: 24446

East Asian (EAS) AF: 0.00134 AC: 51 AN: 37970

South Asian (SAS) AF: 0.00110 AC: 89 AN: 80576

European-Finnish (FIN) AF: 0.000291 AC: 15 AN: 51506

Middle Eastern (MID) AF: 0.000183 AC: 1 AN: 5456

European-Non Finnish (NFE) AF: 0.000373 AC: 401 AN: 1073762

Other (OTH) AF: 0.000524 AC: 30 AN: 57284

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000379 AC: 57 AN: 150338 Hom.: 0 Cov.: 32 AF XY: 0.000423 AC XY: 31 AN XY: 73372

African (AFR) AF: 0.000122 AC: 5 AN: 40954

American (AMR) AF: 0.00172 AC: 26 AN: 15120

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3456

East Asian (EAS) AF: 0.000972 AC: 5 AN: 5142

South Asian (SAS) AF: 0.000845 AC: 4 AN: 4736

European-Finnish (FIN) AF: 0.000197 AC: 2 AN: 10142

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000178 AC: 12 AN: 67500

Other (OTH) AF: 0.00143 AC: 3 AN: 2094

Alfa AF: 0.00460 Hom.: 0

Bravo AF: 0.000348

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.86
Mutation Taster		=100/0	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: rs201453499; hg19: chr22-39713638; COSMIC: COSV53366924; COSMIC: COSV53366924;