rs36014035

Positions:

• chr10-93600270-A-C
• chr10-93600270-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006744.4(RBP4):​c.355+123T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.375 in 871,908 control chromosomes in the GnomAD database, including 64,371 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.39 (12240 hom., cov: 32)
  • Exomes 𝑓: 0.37 (52131 hom.)
• Consequence: RBP4 NM_006744.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.833

Genes affected

RBP4 (HGNC:9922): (retinol binding protein 4) This protein belongs to the lipocalin family and is the specific carrier for retinol (vitamin A alcohol) in the blood. It delivers retinol from the liver stores to the peripheral tissues. In plasma, the RBP-retinol complex interacts with transthyretin which prevents its loss by filtration through the kidney glomeruli. A deficiency of vitamin A blocks secretion of the binding protein posttranslationally and results in defective delivery and supply to the epidermal cells. [provided by RefSeq, Jul 2008]

FFAR4 (HGNC:19061): (free fatty acid receptor 4) This gene encodes a G protein-coupled receptor (GPR) which belongs to the rhodopsin family of GPRs. The encoded protein functions as a receptor for free fatty acids, including omega-3, and participates in suppressing anti-inflammatory responses and insulin sensitizing. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Feb 2012]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 10-93600270-A-C is Benign according to our data. Variant chr10-93600270-A-C is described in ClinVar as [Benign]. Clinvar id is 931422.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.471 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RBP4	NM_006744.4	c.355+123T>G		intron_variant		ENST00000371464.8	NP_006735.2
RBP4	NM_001323517.1	c.355+123T>G		intron_variant			NP_001310446.1
RBP4	NM_001323518.2	c.349+123T>G		intron_variant			NP_001310447.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RBP4	ENST00000371464.8	c.355+123T>G		intron_variant		1	NM_006744.4	ENSP00000360519	P1
RBP4	ENST00000371467.5	c.355+123T>G		intron_variant		5		ENSP00000360522	P1
RBP4	ENST00000371469.2	c.349+123T>G		intron_variant		5		ENSP00000360524
FFAR4	ENST00000604414.1	c.697-3804A>C		intron_variant		3		ENSP00000474477

Frequencies

GnomAD3 genomes AF: 0.393 AC: 59712 AN: 151812 Hom.: 12215 Cov.: 32

Gnomad AFR AF: 0.476

Gnomad AMI AF: 0.287

Gnomad AMR AF: 0.314

Gnomad ASJ AF: 0.449

Gnomad EAS AF: 0.107

Gnomad SAS AF: 0.436

Gnomad FIN AF: 0.343

Gnomad MID AF: 0.484

Gnomad NFE AF: 0.385

Gnomad OTH AF: 0.405

GnomAD4 exome AF: 0.371 AC: 267137 AN: 719978 Hom.: 52131 AF XY: 0.376 AC XY: 144357 AN XY: 384082

Gnomad4 AFR exome AF: 0.475

Gnomad4 AMR exome AF: 0.246

Gnomad4 ASJ exome AF: 0.456

Gnomad4 EAS exome AF: 0.101

Gnomad4 SAS exome AF: 0.436

Gnomad4 FIN exome AF: 0.343

Gnomad4 NFE exome AF: 0.385

Gnomad4 OTH exome AF: 0.390

GnomAD4 genome AF: 0.394 AC: 59798 AN: 151930 Hom.: 12240 Cov.: 32 AF XY: 0.392 AC XY: 29101 AN XY: 74244

Gnomad4 AFR AF: 0.477

Gnomad4 AMR AF: 0.314

Gnomad4 ASJ AF: 0.449

Gnomad4 EAS AF: 0.107

Gnomad4 SAS AF: 0.437

Gnomad4 FIN AF: 0.343

Gnomad4 NFE AF: 0.385

Gnomad4 OTH AF: 0.401

Alfa AF: 0.380 Hom.: 1382

Bravo AF: 0.392

Asia WGS AF: 0.277 AC: 963 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 14, 2021	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Progressive retinal dystrophy due to retinol transport defect Benign:1

Benign, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Dec 20, 2018

This variant was classified as: Benign. This variant was detected in homozygous state. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	6.6
DANN	Benign	0.60

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs36014035; hg19: chr10-95360027; COSMIC: COSV65159762;