12-112405271-C-T

Variant names:

• chr12-112405271-C-T
• rs973688075
• NM_000970.6:c.820G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000970.6(RPL6):​c.820G>A​(p.Val274Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,454,602 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: RPL6 NM_000970.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.388

Genes affected

RPL6 (HGNC:10362): (ribosomal protein L6) This gene encodes a protein component of the 60S ribosomal subunit. This protein can bind specifically to domain C of the tax-responsive enhancer element of human T-cell leukemia virus type 1, and may participate in tax-mediated transactivation of transcription. As is typical for genes encoding ribosomal proteins, there are multiple processed pseudogenes of this gene dispersed throughout the genome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2016]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10766482).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPL6	NM_000970.6	c.820G>A	p.Val274Met	missense_variant	Exon 7 of 7	ENST00000202773.14	NP_000961.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPL6	ENST00000202773.14	c.820G>A	p.Val274Met	missense_variant	Exon 7 of 7	1	NM_000970.6	ENSP00000202773.9
RPL6	ENST00000424576.6	c.820G>A	p.Val274Met	missense_variant	Exon 7 of 7	1		ENSP00000403172.2
RPL6	ENST00000553205.1	n.818G>A		non_coding_transcript_exon_variant	Exon 2 of 2	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1454602 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 723630

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 32942

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 42918

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26042

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39668

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 85356

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53348

Gnomad4 NFE exome AF: 9.01e-7 AC: 1 AN: 1110040

Gnomad4 Remaining exome AF: 0.00 AC: 0 AN: 60004

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 21, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.820G>A (p.V274M) alteration is located in exon 7 (coding exon 6) of the RPL6 gene. This alteration results from a G to A substitution at nucleotide position 820, causing the valine (V) at amino acid position 274 to be replaced by a methionine (M). 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	Benign	0.16
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	9.7
DANN	Benign	0.83
DEOGEN2	Benign	0.077	T;T
Eigen	Benign	-0.99
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.065	N
LIST_S2	Benign	0.85	.;D
M_CAP	Benign	0.0066	T
MetaRNN	Benign	0.11	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	L;L
PrimateAI	Benign	0.36	T
PROVEAN	Benign	0.30	N;N
REVEL	Benign	0.012
Sift	Benign	0.30	T;T
Sift4G	Benign	0.18	T;T
Polyphen		0.0040	B;B
Vest4		0.15
MutPred		0.32		Gain of helix (P = 0.1736);Gain of helix (P = 0.1736);
MVP		0.38
MPC		0.87
ClinPred		0.037	T
GERP RS		-0.37
Varity_R		0.034
gMVP		0.14
Mutation Taster		=97/3	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

Publications

LitVar

Other links and lift over

dbSNP: rs973688075; hg19: chr12-112843075;