rs777620177

Variant names:

• chr10-93592104-C-A
• rs777620177
• NM_006744.4:c.577G>T

Your query was ambiguous. Multiple possible variants found:

• chr10-93592104-C-A
• chr10-93592104-C-G
• chr10-93592104-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 5P and 2B. PM1 PM2 PP2 BP4_Moderate

The NM_006744.4(RBP4):​c.577G>T​(p.Asp193Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D193N) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RBP4 NM_006744.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.604
• Publications: 1 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: Uncertain_significance. The variant received 3 ACMG points.

• PM1: In a chain Plasma retinol-binding protein(1-182) (size 181) in uniprot entity RET4_HUMAN there are 8 pathogenic changes around while only 3 benign (73%) in NM_006744.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 10 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 0.77539 (below the threshold of 3.09). Trascript score misZ: 0.86182 (below the threshold of 3.09). GenCC associations: The gene is linked to progressive retinal dystrophy due to retinol transport defect, microphthalmia, isolated, with coloboma 10, isolated anophthalmia-microphthalmia syndrome, microphthalmia, isolated, with coloboma.
• BP4: Computational evidence support a benign effect (MetaRNN=0.21265805).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RBP4	NM_006744.4	c.577G>T	p.Asp193Tyr	missense_variant	Exon 6 of 6	ENST00000371464.8	NP_006735.2
RBP4	NM_001323517.1	c.577G>T	p.Asp193Tyr	missense_variant	Exon 6 of 6		NP_001310446.1
RBP4	NM_001323518.2	c.571G>T	p.Asp191Tyr	missense_variant	Exon 6 of 6		NP_001310447.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RBP4	ENST00000371464.8	c.577G>T	p.Asp193Tyr	missense_variant	Exon 6 of 6	1	NM_006744.4	ENSP00000360519.3
RBP4	ENST00000371467.5	c.577G>T	p.Asp193Tyr	missense_variant	Exon 6 of 6	5		ENSP00000360522.1
RBP4	ENST00000371469.2	c.571G>T	p.Asp191Tyr	missense_variant	Exon 6 of 6	5		ENSP00000360524.2
FFAR4	ENST00000604414.1	c.697-11970C>A		intron_variant	Intron 2 of 2	3		ENSP00000474477.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.021	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.48	T;T;T;T
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.76	.;T;T;.
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.21	T;T;T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	2.0	M;M;.;.
PhyloP100		0.60
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-2.0	N;N;.;N
REVEL	Benign	0.20
Sift	Uncertain	0.0020	D;D;.;D
Sift4G	Uncertain	0.014	D;D;D;D
Polyphen		0.99	D;D;.;.
Vest4		0.23
MutPred		0.38		Gain of MoRF binding (P = 0.0253);Gain of MoRF binding (P = 0.0253);.;.;
MVP		0.51
MPC		0.86
ClinPred		0.72	D
GERP RS		2.0
Varity_R		0.37
gMVP		0.51
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs777620177; hg19: chr10-95351861;