12-7128343-A-T

Position:

• chr12-7128343-A-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_001329454.2(RBP5):​c.2T>A​(p.Met1?) variant causes a start lost change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: RBP5 NM_001329454.2 start_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.23

Genes affected

RBP5 (HGNC:15847): (retinol binding protein 5) The protein encoded by this gene is a cellular retinol-binding protein expressed highly in kidney and liver. Down-regulation of the encoded protein in hepatocellular carcinoma was associated with large tumor size and poor patient survival rates. [provided by RefSeq, Jul 2016]

RBP5 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RBP5	NM_031491.4	c.149T>A	p.Met50Lys	missense_variant	2/4	ENST00000266560.8	NP_113679.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RBP5	ENST00000266560.8	c.149T>A	p.Met50Lys	missense_variant	2/4	1	NM_031491.4	ENSP00000266560.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000130 AC: 19 AN: 1461884 Hom.: 0 Cov.: 32 AF XY: 0.0000151 AC XY: 11 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000162

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 30, 2022

The c.149T>A (p.M50K) alteration is located in exon 2 (coding exon 2) of the RBP5 gene. This alteration results from a T to A substitution at nucleotide position 149, causing the methionine (M) at amino acid position 50 to be replaced by a lysine (K). 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	Pathogenic	0.83
BayesDel_addAF	Uncertain	0.038	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	21
DANN	Benign	0.82
DEOGEN2	Benign	0.076	T;T
Eigen	Benign	0.048
Eigen_PC	Benign	-0.12
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.67	T;T
M_CAP	Benign	0.014	T
MetaRNN	Pathogenic	0.91	D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	2.9	M;.
PrimateAI	Benign	0.35	T
PROVEAN	Uncertain	-3.8	D;D
REVEL	Benign	0.25
Sift	Uncertain	0.0010	D;D
Sift4G	Benign	0.15	T;T
Polyphen		0.91	P;.
Vest4		0.78
MutPred		0.71		Gain of catalytic residue at M50 (P = 0.0022);Gain of catalytic residue at M50 (P = 0.0022);
MVP		0.19
MPC		1.0
ClinPred		0.99	D
GERP RS		2.1
Varity_R		0.96
gMVP		0.89

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-7280939; COSMIC: COSV99867679; COSMIC: COSV99867679;