chr4-39454554-C-A

Variant names:

• chr4-39454554-C-A
• rs1453715995
• NM_000661.5:c.568G>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_000661.5(RPL9):​c.568G>T​(p.Ala190Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000497 in 1,609,530 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. A190A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: RPL9 NM_000661.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.72
• Publications: 0 publications found

Genes affected

RPL9 (HGNC:10369): (ribosomal protein L9) 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 L6P family of ribosomal proteins. It is located in the cytoplasm. As is typical for genes encoding ribosomal proteins, there are multiple processed pseudogenes of this gene dispersed through the genome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2016]

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.20446375).
• BS2: High AC in GnomAdExome4 at 7 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000661.5. 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
	RPL9	NM_000661.5	MANE Select	c.568G>T	p.Ala190Ser	missense	Exon 7 of 8	NP_000652.2
	RPL9	NM_001024921.4		c.568G>T	p.Ala190Ser	missense	Exon 7 of 8	NP_001020092.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPL9	ENST00000295955.14	TSL:1 MANE Select	c.568G>T	p.Ala190Ser	missense	Exon 7 of 8	ENSP00000346022.7
	RPL9	ENST00000449470.6	TSL:1	c.568G>T	p.Ala190Ser	missense	Exon 6 of 7	ENSP00000400467.2
	RPL9	ENST00000503277.6	TSL:2	c.652G>T	p.Ala218Ser	missense	Exon 6 of 7	ENSP00000494836.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152210 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000480 AC: 7 AN: 1457320 Hom.: 0 Cov.: 30 AF XY: 0.00000552 AC XY: 4 AN XY: 725004

African (AFR) AF: 0.00 AC: 0 AN: 33326

American (AMR) AF: 0.00 AC: 0 AN: 44322

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26004

East Asian (EAS) AF: 0.00 AC: 0 AN: 39580

South Asian (SAS) AF: 0.00 AC: 0 AN: 85718

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53356

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4960

European-Non Finnish (NFE) AF: 0.00000631 AC: 7 AN: 1109916

Other (OTH) AF: 0.00 AC: 0 AN: 60138

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152210 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74352

African (AFR) AF: 0.00 AC: 0 AN: 41460

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	20
DANN	Benign	0.96
DEOGEN2	Benign	0.034	T
Eigen	Benign	-0.015
Eigen_PC	Benign	0.058
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.0021	T
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		1.7
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.45	N
REVEL	Benign	0.028
Sift	Benign	0.46	T
Sift4G	Benign	0.56	T
Polyphen		0.0	B
Vest4		0.12
MVP		0.34
MPC		0.72
ClinPred		0.72	D
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.12
gMVP		0.34
Mutation Taster		=84/16	polymorphism

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: rs1453715995; hg19: chr4-39456174;