NM_012423.4:c.523A>C

Variant names:

• chr19-49491545-A-C
• rs779643610
• NM_012423.4:c.523A>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_012423.4(RPL13A):​c.523A>C​(p.Met175Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 18/23 in silico tools predict 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M175V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0016 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RPL13A NM_012423.4 missense, splice_region
• Scores: Splicing: ADA: 0.0001752
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.55
• Publications: 0 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]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.12617975).

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.523A>C	p.Met175Leu	missense splice_region	Exon 7 of 8	NP_036555.1	P40429
	RPL13A	NM_001270491.2		c.340A>C	p.Met114Leu	missense splice_region	Exon 6 of 7	NP_001257420.1	Q8J015
	RPL13A	NR_073024.2		n.535A>C		splice_region non_coding_transcript_exon	Exon 7 of 8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPL13A	ENST00000391857.9	TSL:1 MANE Select	c.523A>C	p.Met175Leu	missense splice_region	Exon 7 of 8	ENSP00000375730.4	P40429
	RPL13A	ENST00000624069.3	TSL:1	n.*366A>C		splice_region non_coding_transcript_exon	Exon 7 of 8	ENSP00000485546.1	A0A096LPE0
	RPL13A	ENST00000624069.3	TSL:1	n.*366A>C		3_prime_UTR	Exon 7 of 8	ENSP00000485546.1	A0A096LPE0

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151678 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000195

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000951

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00159 AC: 2193 AN: 1383038 Hom.: 0 Cov.: 33 AF XY: 0.00149 AC XY: 1022 AN XY: 683860

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

African (AFR) AF: 0.00135 AC: 43 AN: 31928

American (AMR) AF: 0.0000270 AC: 1 AN: 37014

Ashkenazi Jewish (ASJ) AF: 0.000596 AC: 15 AN: 25178

East Asian (EAS) AF: 0.000300 AC: 11 AN: 36672

South Asian (SAS) AF: 0.000588 AC: 47 AN: 79980

European-Finnish (FIN) AF: 0.0000777 AC: 3 AN: 38634

Middle Eastern (MID) AF: 0.000705 AC: 4 AN: 5670

European-Non Finnish (NFE) AF: 0.00188 AC: 2016 AN: 1070098

Other (OTH) AF: 0.000916 AC: 53 AN: 57864

⚠️ 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 Data not reliable, filtered out with message: AS_VQSR AF: 0.0000132 AC: 2 AN: 151794 Hom.: 0 Cov.: 31 AF XY: 0.0000270 AC XY: 2 AN XY: 74196

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

African (AFR) AF: 0.00 AC: 0 AN: 41478

American (AMR) AF: 0.00 AC: 0 AN: 15214

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.000195 AC: 1 AN: 5128

South Asian (SAS) AF: 0.00 AC: 0 AN: 4800

European-Finnish (FIN) AF: 0.0000951 AC: 1 AN: 10516

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67888

Other (OTH) AF: 0.00 AC: 0 AN: 2104

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0000000000983081), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.070	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	18
DANN	Benign	0.88
DEOGEN2	Benign	0.023	T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.23
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.35	T
M_CAP	Benign	0.0051	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.085	N
PhyloP100		1.6
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.53	N
REVEL	Benign	0.21
Sift	Benign	0.36	T
Sift4G	Benign	0.41	T
Polyphen		0.0	B
Vest4		0.26
MutPred		0.34		Loss of methylation at K170 (P = 0.0687)
MVP		0.46
MPC		0.44
ClinPred		0.97	D
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.049
gMVP		0.60
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00018
dbscSNV1_RF	Benign	0.0040
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: rs779643610; hg19: chr19-49994802;