8-73291828-G-A

Variant names:

• chr8-73291828-G-A
• rs1340792595
• NM_000971.4:c.373C>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000971.4(RPL7):​c.373C>T​(p.Leu125Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,660 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: RPL7 NM_000971.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.22

Genes affected

RPL7 (HGNC:10363): (ribosomal protein L7) 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 L30P family of ribosomal proteins. It contains an N-terminal basic region-leucine zipper (BZIP)-like domain and the RNP consensus submotif RNP2. In vitro the BZIP-like domain mediates homodimerization and stable binding to DNA and RNA, with a preference for 28S rRNA and mRNA. The protein can inhibit cell-free translation of mRNAs, suggesting that it plays a regulatory role in the translation apparatus. It is located in the cytoplasm. The protein has been shown to be an autoantigen in patients with systemic autoimmune diseases, such as systemic lupus erythematosus. As is typical for genes encoding ribosomal proteins, there are multiple processed pseudogenes of this gene dispersed through the genome. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPL7	NM_000971.4	c.373C>T	p.Leu125Phe	missense_variant	Exon 4 of 7	ENST00000352983.7	NP_000962.2
RPL7	NM_001363737.2	c.253C>T	p.Leu85Phe	missense_variant	Exon 4 of 7		NP_001350666.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPL7	ENST00000352983.7	c.373C>T	p.Leu125Phe	missense_variant	Exon 4 of 7	1	NM_000971.4	ENSP00000339795.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460660 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 726376

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 02, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.373C>T (p.L125F) alteration is located in exon 4 (coding exon 4) of the RPL7 gene. This alteration results from a C to T substitution at nucleotide position 373, causing the leucine (L) at amino acid position 125 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.62	.;D;.;.;.;T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.87	.;D;.;D;T;T
M_CAP	Benign	0.038	D
MetaRNN	Uncertain	0.63	D;D;D;D;D;D
MetaSVM	Uncertain	0.051	D
MutationAssessor	Uncertain	2.7	.;M;.;.;.;.
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-3.4	D;D;D;D;D;D
REVEL	Benign	0.26
Sift	Uncertain	0.019	D;D;D;D;D;D
Sift4G	Uncertain	0.052	T;T;T;T;.;.
Polyphen		0.097	.;B;.;.;.;.
Vest4		0.29
MutPred		0.53		.;Gain of methylation at K124 (P = 0.032);.;.;.;.;
MVP		0.57
MPC		0.49
ClinPred		0.91	D
GERP RS		4.8
Varity_R		0.40
gMVP		0.88

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: rs1340792595; hg19: chr8-74204063;