19-49491420-C-A

Variant names:

• chr19-49491420-C-A
• rs115089990
• NM_012423.4:c.403-5C>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP3 BS2

The NM_012423.4(RPL13A):​c.403-5C>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000995 in 1,004,596 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 15)
  • Exomes 𝑓: 0.000010 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RPL13A NM_012423.4 splice_region, intron
• Scores: Splicing: ADA: 0.9977
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0200
• Publications: 3 publications found

Genes affected

RPL13A (HGNC:10304): (ribosomal protein L13a) Ribosomes, the organelles 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 member of the L13P family of ribosomal proteins that is a component of the 60S subunit. The encoded protein also plays a role in the repression of inflammatory genes as a component of the IFN-gamma-activated inhibitor of translation (GAIT) complex. This gene is co-transcribed with the small nucleolar RNA genes U32, U33, U34, and U35, which are located in the second, fourth, fifth, and sixth introns, respectively. As is typical for genes encoding ribosomal proteins, there are multiple processed pseudogenes of this gene dispersed throughout the genome. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Jul 2012]

SNORD35A (HGNC:10162): (small nucleolar RNA, C/D box 35A) Predicted to act upstream of or within glucose metabolic process; insulin secretion; and reactive oxygen species metabolic process. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BS2: High AC in GnomAdExome4 at 10 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012423.4. 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
	RPL13A	NM_012423.4	MANE Select	c.403-5C>A		splice_region intron	N/A	NP_036555.1	P40429
	RPL13A	NM_001270491.2		c.220-5C>A		splice_region intron	N/A	NP_001257420.1	Q8J015
	RPL13A	NR_073024.2		n.415-5C>A		splice_region intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPL13A	ENST00000391857.9	TSL:1 MANE Select	c.403-5C>A		splice_region intron	N/A	ENSP00000375730.4	P40429
	RPL13A	ENST00000624069.3	TSL:1	n.*246-5C>A		splice_region intron	N/A	ENSP00000485546.1	A0A096LPE0
	RPL13A	ENST00000467825.2	TSL:5	c.421-5C>A		splice_region intron	N/A	ENSP00000470037.2	M0QYS1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 67430 Hom.: 0 Cov.: 15

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000995 AC: 10 AN: 1004596 Hom.: 0 Cov.: 22 AF XY: 0.00000796 AC XY: 4 AN XY: 502786

African (AFR) AF: 0.00 AC: 0 AN: 21730

American (AMR) AF: 0.00 AC: 0 AN: 29242

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19856

East Asian (EAS) AF: 0.00 AC: 0 AN: 27818

South Asian (SAS) AF: 0.0000146 AC: 1 AN: 68640

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 25220

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3048

European-Non Finnish (NFE) AF: 0.0000104 AC: 8 AN: 766908

Other (OTH) AF: 0.0000237 AC: 1 AN: 42134

GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 67430 Hom.: 0 Cov.: 15 AF XY: 0.00 AC XY: 0 AN XY: 34140

African (AFR) AF: 0.00 AC: 0 AN: 15888

American (AMR) AF: 0.00 AC: 0 AN: 8180

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1586

East Asian (EAS) AF: 0.00 AC: 0 AN: 2788

South Asian (SAS) AF: 0.00 AC: 0 AN: 1558

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7664

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 196

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 28324

Other (OTH) AF: 0.00 AC: 0 AN: 810

Alfa AF: 0.00 Hom.: 17

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	20
DANN	Benign	0.82
PhyloP100		0.020

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.83
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.99		Position offset: 2

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

Other links and lift over

dbSNP: rs115089990; hg19: chr19-49994677;