chr10-93594060-C-G

Variant names:

• chr10-93594060-C-G
• rs12265684
• NM_006744.4:c.356-25G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006744.4(RBP4):​c.356-25G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.189 in 1,607,644 control chromosomes in the GnomAD database, including 31,431 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.23 (4408 hom., cov: 32)
  • Exomes 𝑓: 0.18 (27023 hom.)
• Consequence: RBP4 NM_006744.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.470
• Publications: 13 publications found

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

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 3 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 10-93594060-C-G is Benign according to our data. Variant chr10-93594060-C-G is described in ClinVar as [Benign]. Clinvar id is 1277035.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.337 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RBP4	NM_006744.4	c.356-25G>C		intron_variant	Intron 4 of 5	ENST00000371464.8	NP_006735.2
RBP4	NM_001323517.1	c.356-25G>C		intron_variant	Intron 4 of 5		NP_001310446.1
RBP4	NM_001323518.2	c.350-25G>C		intron_variant	Intron 4 of 5		NP_001310447.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RBP4	ENST00000371464.8	c.356-25G>C		intron_variant	Intron 4 of 5	1	NM_006744.4	ENSP00000360519.3
FFAR4	ENST00000604414.1	c.697-10014C>G		intron_variant	Intron 2 of 2	3		ENSP00000474477.1
RBP4	ENST00000371467.5	c.356-25G>C		intron_variant	Intron 4 of 5	5		ENSP00000360522.1
RBP4	ENST00000371469.2	c.350-25G>C		intron_variant	Intron 4 of 5	5		ENSP00000360524.2

Frequencies

GnomAD3 genomes AF: 0.226 AC: 34355 AN: 152000 Hom.: 4400 Cov.: 32

Gnomad AFR AF: 0.342

Gnomad AMI AF: 0.0625

Gnomad AMR AF: 0.193

Gnomad ASJ AF: 0.250

Gnomad EAS AF: 0.100

Gnomad SAS AF: 0.342

Gnomad FIN AF: 0.160

Gnomad MID AF: 0.294

Gnomad NFE AF: 0.175

Gnomad OTH AF: 0.247

GnomAD2 exomes AF: 0.201 AC: 48935 AN: 242910 AF XY: 0.210

Gnomad AFR exome AF: 0.345

Gnomad AMR exome AF: 0.146

Gnomad ASJ exome AF: 0.259

Gnomad EAS exome AF: 0.105

Gnomad FIN exome AF: 0.159

Gnomad NFE exome AF: 0.179

Gnomad OTH exome AF: 0.204

GnomAD4 exome AF: 0.185 AC: 268929 AN: 1455526 Hom.: 27023 Cov.: 31 AF XY: 0.189 AC XY: 137226 AN XY: 724422

African (AFR) AF: 0.354 AC: 11806 AN: 33382

American (AMR) AF: 0.150 AC: 6704 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.256 AC: 6698 AN: 26122

East Asian (EAS) AF: 0.101 AC: 4009 AN: 39668

South Asian (SAS) AF: 0.328 AC: 28297 AN: 86162

European-Finnish (FIN) AF: 0.153 AC: 7809 AN: 50966

Middle Eastern (MID) AF: 0.273 AC: 1569 AN: 5754

European-Non Finnish (NFE) AF: 0.171 AC: 189940 AN: 1108534

Other (OTH) AF: 0.201 AC: 12097 AN: 60226

GnomAD4 genome AF: 0.226 AC: 34412 AN: 152118 Hom.: 4408 Cov.: 32 AF XY: 0.229 AC XY: 17020 AN XY: 74378

African (AFR) AF: 0.342 AC: 14170 AN: 41452

American (AMR) AF: 0.193 AC: 2958 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.250 AC: 868 AN: 3472

East Asian (EAS) AF: 0.101 AC: 520 AN: 5162

South Asian (SAS) AF: 0.343 AC: 1656 AN: 4826

European-Finnish (FIN) AF: 0.160 AC: 1697 AN: 10580

Middle Eastern (MID) AF: 0.296 AC: 87 AN: 294

European-Non Finnish (NFE) AF: 0.175 AC: 11880 AN: 68006

Other (OTH) AF: 0.245 AC: 519 AN: 2116

Alfa AF: 0.132 Hom.: 332

Bravo AF: 0.232

Asia WGS AF: 0.209 AC: 727 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

May 14, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Progressive retinal dystrophy due to retinol transport defect Benign:1

Nov 07, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Microphthalmia, isolated, with coloboma 10 Benign:1

Nov 07, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	4.8
DANN	Benign	0.33
PhyloP100		0.47
BranchPoint Hunter		3.0
Mutation Taster		=100/0	polymorphism (auto)

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: rs12265684; hg19: chr10-95353817; COSMIC: COSV65159758; COSMIC: COSV65159758;