NM_001319236.2:c.16A>G

Variant names:

• chr4-108621975-A-G
• rs1725797806
• NM_001319236.2:c.16A>G

Variant summary

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

The NM_001319236.2(RPL34):​c.16A>G​(p.Thr6Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000703 in 1,422,548 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. T6P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: RPL34 NM_001319236.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.89
• 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.16A>G	p.Thr6Ala	missense	Exon 2 of 5	NP_001306165.1	P49207
	RPL34	NM_000995.5		c.16A>G	p.Thr6Ala	missense	Exon 2 of 6	NP_000986.2
	RPL34	NM_001319232.2		c.16A>G	p.Thr6Ala	missense	Exon 3 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.16A>G	p.Thr6Ala	missense	Exon 2 of 5	ENSP00000378162.3	P49207
	RPL34	ENST00000394668.3	TSL:1	c.16A>G	p.Thr6Ala	missense	Exon 2 of 6	ENSP00000378163.2	P49207
	RPL34	ENST00000926079.1		c.16A>G	p.Thr6Ala	missense	Exon 2 of 5	ENSP00000596138.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.03e-7 AC: 1 AN: 1422548 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 708962

⚠️ 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: 32640

American (AMR) AF: 0.00 AC: 0 AN: 44474

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25658

East Asian (EAS) AF: 0.00 AC: 0 AN: 38996

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85478

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52808

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4808

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1078764

Other (OTH) AF: 0.00 AC: 0 AN: 58922

⚠️ 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	Pathogenic	0.79
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.46	T
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.026	D
MetaRNN	Uncertain	0.68	D
MetaSVM	Benign	-0.47	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		8.9
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-3.4	D
REVEL	Uncertain	0.48
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.030	D
Polyphen		0.0070	B
Vest4		0.81
MutPred		0.60		Gain of glycosylation at T6 (P = 0.0069)
MVP		0.79
MPC		0.88
ClinPred		0.99	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.45
gMVP		0.85
Mutation Taster		=10/90	disease causing

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: rs1725797806; hg19: chr4-109543131;