4-108622163-C-G

Variant names:

• chr4-108622163-C-G
• rs748376623
• NM_001319236.2:c.124C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001319236.2(RPL34):​c.124C>G​(p.Pro42Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,036 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P42S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RPL34 NM_001319236.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.51
• Publications: 0 publications found

Genes affected

RPL34 (HGNC:10340): (ribosomal protein L34) 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 L34E family of ribosomal proteins. It is located in the cytoplasm. This gene originally was thought to be located at 17q21, but it has been mapped to 4q. Overexpression of this gene has been observed in some cancer cells. Alternative splicing results in multiple transcript variants, all encoding the same isoform. As is typical for genes encoding ribosomal proteins, there are multiple processed pseudogenes of this gene dispersed through the genome. [provided by RefSeq, Feb 2016]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001319236.2. 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
	RPL34	NM_001319236.2	MANE Select	c.124C>G	p.Pro42Ala	missense	Exon 3 of 5	NP_001306165.1	P49207
	RPL34	NM_000995.5		c.124C>G	p.Pro42Ala	missense	Exon 3 of 6	NP_000986.2
	RPL34	NM_001319232.2		c.124C>G	p.Pro42Ala	missense	Exon 4 of 6	NP_001306161.1	P49207

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPL34	ENST00000394667.8	TSL:1 MANE Select	c.124C>G	p.Pro42Ala	missense	Exon 3 of 5	ENSP00000378162.3	P49207
	RPL34	ENST00000394668.3	TSL:1	c.124C>G	p.Pro42Ala	missense	Exon 3 of 6	ENSP00000378163.2	P49207
	RPL34	ENST00000504231.1	TSL:1	n.121C>G		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000400 AC: 1 AN: 249974 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461036 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726862

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

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52672

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111920

Other (OTH) AF: 0.00 AC: 0 AN: 60390

⚠️ 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 Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	0.060
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.27	T
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.0085	T
MetaRNN	Uncertain	0.65	D
MetaSVM	Benign	-0.57	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		7.5
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-6.6	D
REVEL	Uncertain	0.32
Sift	Uncertain	0.013	D
Sift4G	Uncertain	0.034	D
Polyphen		0.39	B
Vest4		0.70
MutPred		0.58		Loss of glycosylation at P42 (P = 0.0403)
MVP		0.52
MPC		1.7
ClinPred		0.98	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.52
gMVP		0.68
Mutation Taster		=51/49	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs748376623; hg19: chr4-109543319;