chr2-101004199-G-A

Position:

• chr2-101004199-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_000993.5(RPL31):​c.149G>A​(p.Arg50Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000929 in 1,613,898 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: RPL31 NM_000993.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.73

Genes affected

RPL31 (HGNC:10334): (ribosomal protein L31) 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 ribosomal protein that is a component of the 60S subunit. The protein belongs to the L31E family of ribosomal proteins. It is located in the cytoplasm. Higher levels of expression of this gene in familial adenomatous polyps compared to matched normal tissues have been observed. As is typical for genes encoding ribosomal proteins, there are multiple processed pseudogenes of this gene dispersed through the genome. Alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RPL31	NM_000993.5	c.149G>A	p.Arg50Gln	missense_variant	3/5	ENST00000264258.8	NP_000984.1
RPL31	NM_001098577.3	c.149G>A	p.Arg50Gln	missense_variant	3/5		NP_001092047.1
RPL31	NM_001099693.2	c.149G>A	p.Arg50Gln	missense_variant	3/4		NP_001093163.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RPL31	ENST00000264258.8	c.149G>A	p.Arg50Gln	missense_variant	3/5	1	NM_000993.5	ENSP00000264258.3

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152128 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.000956

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1461770 Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6 AN XY: 727186

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000899

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152128 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74312

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000956

Bravo AF: 0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 22, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. This variant has not been reported in the literature in individuals affected with RPL31-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 50 of the RPL31 protein (p.Arg50Gln). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	T;T;.;.;T;T;.;.;T
Eigen	Benign	-0.00021
Eigen_PC	Benign	0.099
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.82	.;.;T;T;T;T;T;T;T
M_CAP	Benign	0.0086	T
MetaRNN	Uncertain	0.58	D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	0.91	L;.;L;L;L;.;.;.;.
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-1.7	N;N;N;N;N;N;N;N;N
REVEL	Benign	0.26
Sift	Benign	0.28	T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.29	T;T;T;T;T;T;T;T;T
Polyphen		0.0010	B;B;.;.;B;B;P;.;B
Vest4		0.76
MutPred		0.51		Loss of MoRF binding (P = 0.0475);Loss of MoRF binding (P = 0.0475);Loss of MoRF binding (P = 0.0475);Loss of MoRF binding (P = 0.0475);Loss of MoRF binding (P = 0.0475);Loss of MoRF binding (P = 0.0475);Loss of MoRF binding (P = 0.0475);Loss of MoRF binding (P = 0.0475);Loss of MoRF binding (P = 0.0475);
MVP		0.88
MPC		1.3
ClinPred		0.99	D
GERP RS		3.3
Varity_R		0.24
gMVP		0.81

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

Publications

LitVar

Other links and lift over

dbSNP: rs1339147334; hg19: chr2-101620661;