rs1725797806

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr4-108621975-A-C
• chr4-108621975-A-G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The NM_001319236.2(RPL34):​c.16A>C​(p.Thr6Pro) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. T6T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 33)
  • Exomes 𝑓: 0.017 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RPL34 NM_001319236.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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 1 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.752

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>C	p.Thr6Pro	missense	Exon 2 of 5	NP_001306165.1	P49207
	RPL34	NM_000995.5		c.16A>C	p.Thr6Pro	missense	Exon 2 of 6	NP_000986.2
	RPL34	NM_001319232.2		c.16A>C	p.Thr6Pro	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>C	p.Thr6Pro	missense	Exon 2 of 5	ENSP00000378162.3	P49207
	RPL34	ENST00000394668.3	TSL:1	c.16A>C	p.Thr6Pro	missense	Exon 2 of 6	ENSP00000378163.2	P49207
	RPL34	ENST00000926079.1		c.16A>C	p.Thr6Pro	missense	Exon 2 of 5	ENSP00000596138.1

Frequencies

GnomAD3 genomes AF: 0.000250 AC: 38 AN: 151826 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00155

Gnomad SAS AF: 0.000832

Gnomad FIN AF: 0.000285

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0172 AC: 23812 AN: 1387564 Hom.: 0 Cov.: 29 AF XY: 0.0161 AC XY: 11164 AN XY: 692486

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

African (AFR) AF: 0.0146 AC: 466 AN: 31940

American (AMR) AF: 0.00101 AC: 45 AN: 44340

Ashkenazi Jewish (ASJ) AF: 0.00747 AC: 189 AN: 25310

East Asian (EAS) AF: 0.00502 AC: 193 AN: 38434

South Asian (SAS) AF: 0.00505 AC: 428 AN: 84806

European-Finnish (FIN) AF: 0.00195 AC: 102 AN: 52428

Middle Eastern (MID) AF: 0.0110 AC: 52 AN: 4722

European-Non Finnish (NFE) AF: 0.0206 AC: 21577 AN: 1047942

Other (OTH) AF: 0.0132 AC: 760 AN: 57642

⚠️ 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 Data not reliable, filtered out with message: AS_VQSR AF: 0.000244 AC: 37 AN: 151944 Hom.: 0 Cov.: 33 AF XY: 0.000242 AC XY: 18 AN XY: 74264

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

African (AFR) AF: 0.0000482 AC: 2 AN: 41516

American (AMR) AF: 0.000131 AC: 2 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00155 AC: 8 AN: 5150

South Asian (SAS) AF: 0.000833 AC: 4 AN: 4804

European-Finnish (FIN) AF: 0.000285 AC: 3 AN: 10542

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000265 AC: 18 AN: 67872

Other (OTH) AF: 0.00 AC: 0 AN: 2110

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.50	D
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.087	D
MetaRNN	Pathogenic	0.75	D
MetaSVM	Uncertain	0.26	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		8.9
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-4.3	D
REVEL	Pathogenic	0.71
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.90	P
Vest4		0.66
MutPred		0.61		Gain of glycosylation at T6 (P = 0.0069)
MVP		0.76
MPC		2.1
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.87
gMVP		0.90
Mutation Taster		=12/88	disease causing

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

Other links and lift over

dbSNP: rs1725797806; hg19: chr4-109543131; COSMIC: COSV108924277; COSMIC: COSV108924277;