8-37863094-G-T

Variant names:

• chr8-37863094-G-T
• rs1806274356
• NM_001002814.3:c.3653C>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001002814.3(RAB11FIP1):​c.3653C>A​(p.Pro1218His) variant causes a missense change. The variant allele was found at a frequency of 0.00000479 in 1,460,094 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: RAB11FIP1 NM_001002814.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.10

Genes affected

RAB11FIP1 (HGNC:30265): (RAB11 family interacting protein 1) This gene encodes one of the Rab11-family interacting proteins (Rab11-FIPs), which play a role in the Rab-11 mediated recycling of vesicles. The encoded protein may be involved in endocytic sorting, trafficking of proteins including integrin subunits and epidermal growth factor receptor (EGFR), and transport between the recycling endosome and the trans-Golgi network. Alternative splicing results in multiple transcript variants. A pseudogene is described on the X chromosome. [provided by RefSeq, Dec 2013]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32204977).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAB11FIP1	NM_001002814.3	c.3653C>A	p.Pro1218His	missense_variant	Exon 6 of 6	ENST00000330843.9	NP_001002814.2
RAB11FIP1	NM_025151.5	c.1751C>A	p.Pro584His	missense_variant	Exon 5 of 5		NP_079427.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAB11FIP1	ENST00000330843.9	c.3653C>A	p.Pro1218His	missense_variant	Exon 6 of 6	1	NM_001002814.3	ENSP00000331342.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1460094 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 726330

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: 0.00000630

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 12, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3653C>A (p.P1218H) alteration is located in exon 6 (coding exon 6) of the RAB11FIP1 gene. This alteration results from a C to A substitution at nucleotide position 3653, causing the proline (P) at amino acid position 1218 to be replaced by a histidine (H). 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	Uncertain	0.47
BayesDel_addAF	Uncertain	0.042	T
BayesDel_noAF	Benign	-0.18
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.084	.;T;T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.87	D;D;D
M_CAP	Benign	0.057	D
MetaRNN	Benign	0.32	T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.6	.;L;.
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-2.6	D;D;D
REVEL	Benign	0.16
Sift	Uncertain	0.0050	D;D;D
Sift4G	Benign	0.092	T;D;T
Polyphen		0.74	P;P;D
Vest4		0.42
MutPred		0.24		.;Loss of glycosylation at P1218 (P = 0.0363);.;
MVP		0.55
MPC		0.45
ClinPred		0.99	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.52
gMVP		0.42

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1806274356; hg19: chr8-37720612;