19-49491421-G-A

Variant names:

• chr19-49491421-G-A
• rs115924751
• NM_012423.4:c.403-4G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_012423.4(RPL13A):​c.403-4G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.033 (20 hom., cov: 0)
  • Exomes 𝑓: 0.0086 (53 hom.)
• Consequence: RPL13A NM_012423.4 splice_region, intron
• Scores: Splicing: ADA: 0.00002410
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.55

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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 19-49491421-G-A is Benign according to our data. Variant chr19-49491421-G-A is described in ClinVar as [Benign]. Clinvar id is 775419.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-49491421-G-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0984 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPL13A	NM_012423.4	c.403-4G>A		splice_region_variant, intron_variant	Intron 6 of 7	ENST00000391857.9	NP_036555.1
RPL13A	NM_001270491.2	c.220-4G>A		splice_region_variant, intron_variant	Intron 5 of 6		NP_001257420.1
RPL13A	NR_073024.2	n.415-4G>A		splice_region_variant, intron_variant	Intron 6 of 7
SNORD35A	NR_000018.1	n.*161G>A		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPL13A	ENST00000391857.9	c.403-4G>A		splice_region_variant, intron_variant	Intron 6 of 7	1	NM_012423.4	ENSP00000375730.4

Frequencies

GnomAD3 genomes AF: 0.0330 AC: 517 AN: 15690 Hom.: 20 Cov.: 0

Gnomad AFR AF: 0.106

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0152

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: 0.000380

Gnomad OTH AF: 0.0135

GnomAD2 exomes AF: 0.0188 AC: 391 AN: 20758 AF XY: 0.0155

Gnomad AFR exome AF: 0.173

Gnomad AMR exome AF: 0.0126

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00127

Gnomad OTH exome AF: 0.0141

GnomAD4 exome AF: 0.00859 AC: 1439 AN: 167502 Hom.: 53 Cov.: 5 AF XY: 0.00759 AC XY: 640 AN XY: 84290

Gnomad4 AFR exome AF: 0.164 AC: 1173 AN: 7156

Gnomad4 AMR exome AF: 0.0106 AC: 74 AN: 6974

Gnomad4 ASJ exome AF: 0.000244 AC: 1 AN: 4104

Gnomad4 EAS exome AF: 0.000250 AC: 2 AN: 7998

Gnomad4 SAS exome AF: 0.000675 AC: 7 AN: 10376

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 5732

Gnomad4 NFE exome AF: 0.000309 AC: 36 AN: 116492

Gnomad4 Remaining exome AF: 0.0169 AC: 136 AN: 8026

GnomAD4 genome AF: 0.0331 AC: 520 AN: 15712 Hom.: 20 Cov.: 0 AF XY: 0.0409 AC XY: 280 AN XY: 6846

Gnomad4 AFR AF: 0.106 AC: 0.106125 AN: 0.106125

Gnomad4 AMR AF: 0.0151 AC: 0.0150943 AN: 0.0150943

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.000379 AC: 0.000379459 AN: 0.000379459

Gnomad4 OTH AF: 0.0135 AC: 0.0135135 AN: 0.0135135

Alfa AF: 0.00157 Hom.: 0

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 05, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.43
DANN	Benign	0.84
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000024
dbscSNV1_RF	Benign	0.0
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: rs115924751; hg19: chr19-49994678;