2-101004190-A-G

Variant names:

• chr2-101004190-A-G
• rs1418315642
• NM_000993.5:c.140A>G

Variant summary

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

The NM_000993.5(RPL31):​c.140A>G​(p.Lys47Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,613,940 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: 0.0000041 (0 hom.)
• Consequence: RPL31 NM_000993.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 8.92

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 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPL31	NM_000993.5	c.140A>G	p.Lys47Arg	missense_variant	Exon 3 of 5	ENST00000264258.8	NP_000984.1
RPL31	NM_001098577.3	c.140A>G	p.Lys47Arg	missense_variant	Exon 3 of 5		NP_001092047.1
RPL31	NM_001099693.2	c.140A>G	p.Lys47Arg	missense_variant	Exon 3 of 4		NP_001093163.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPL31	ENST00000264258.8	c.140A>G	p.Lys47Arg	missense_variant	Exon 3 of 5	1	NM_000993.5	ENSP00000264258.3

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152190 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461750 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727170

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152190 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74348

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

May 04, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.140A>G (p.K47R) alteration is located in exon 3 (coding exon 2) of the RPL31 gene. This alteration results from a A to G substitution at nucleotide position 140, causing the lysine (K) at amino acid position 47 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Apr 17, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. ClinVar contains an entry for this variant (Variation ID: 2287297). This variant has not been reported in the literature in individuals affected with RPL31-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.01%). This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 47 of the RPL31 protein (p.Lys47Arg). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	T;T;.;.;T;T;.;.;T
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.79	.;.;T;T;T;T;T;T;T
M_CAP	Benign	0.012	T
MetaRNN	Uncertain	0.54	D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.33	T
MutationAssessor	Benign	1.9	L;.;L;L;L;.;.;.;.
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-2.5	N;N;N;N;N;D;N;D;N
REVEL	Uncertain	0.35
Sift	Benign	0.047	D;D;D;T;D;T;D;D;D
Sift4G	Benign	0.13	T;T;T;T;T;T;T;T;T
Polyphen		0.021	B;B;.;.;B;B;B;.;B
Vest4		0.54
MVP		0.68
MPC		1.0
ClinPred		0.98	D
GERP RS		4.0
Varity_R		0.28
gMVP		0.66

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: rs1418315642; hg19: chr2-101620652;