11-61904766-G-C

Position:

• chr11-61904766-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_013401.4(RAB3IL1):​c.774C>G​(p.Phe258Leu) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: RAB3IL1 NM_013401.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.58

Genes affected

RAB3IL1 (HGNC:9780): (RAB3A interacting protein like 1) This gene encodes a guanine nucleotide exchange factor for the ras-related protein Rab3A. The encoded protein binds Rab3a and the inositol hexakisphosphate kinase InsP6K1. Alternative splicing results in multiple transcript variants. A related pseudogene has been identified on chromosome 7. [provided by RefSeq, Nov 2012]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.916

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAB3IL1	NM_013401.4	c.774C>G	p.Phe258Leu	missense_variant	6/10	ENST00000394836.7	NP_037533.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAB3IL1	ENST00000394836.7	c.774C>G	p.Phe258Leu	missense_variant	6/10	1	NM_013401.4	ENSP00000378313.2
RAB3IL1	ENST00000301773.9	c.696C>G	p.Phe232Leu	missense_variant	5/9	1		ENSP00000301773.5
RAB3IL1	ENST00000531922.2	c.1059C>G	p.Phe353Leu	missense_variant	7/11	3		ENSP00000435444.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 33

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

Dec 13, 2022

The c.774C>G (p.F258L) alteration is located in exon 6 (coding exon 6) of the RAB3IL1 gene. This alteration results from a C to G substitution at nucleotide position 774, causing the phenylalanine (F) at amino acid position 258 to be replaced by a leucine (L). 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	0.99
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.38	T;.
Eigen	Benign	0.19
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Benign	0.033	D
MetaRNN	Pathogenic	0.92	D;D
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.5	L;.
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-5.7	D;D
REVEL	Benign	0.26
Sift	Benign	0.053	T;T
Sift4G	Benign	0.072	T;T
Polyphen		1.0	D;P
Vest4		0.77
MutPred		0.82		Gain of helix (P = 0.1736);.;
MVP		0.79
MPC		0.50
ClinPred		0.99	D
GERP RS		2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.58
gMVP		0.67

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: chr11-61672238;