1-174252533-A-G

Position:

• chr1-174252533-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001366446.1(RABGAP1L):​c.929A>G​(p.Glu310Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RABGAP1L NM_001366446.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.95

Genes affected

RABGAP1L (HGNC:24663): (RAB GTPase activating protein 1 like) Enables GTPase activator activity and small GTPase binding activity. Acts upstream of or within regulation of protein localization. Located in Golgi apparatus; early endosome; and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RABGAP1L	NM_001366446.1	c.929A>G	p.Glu310Gly	missense_variant	7/26	ENST00000681986.1	NP_001353375.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RABGAP1L	ENST00000681986.1	c.929A>G	p.Glu310Gly	missense_variant	7/26		NM_001366446.1	ENSP00000507884	P2
RABGAP1L	ENST00000357444.10	c.818A>G	p.Glu273Gly	missense_variant	7/14	1		ENSP00000350027
RABGAP1L	ENST00000457696.1	c.965A>G	p.Glu322Gly	missense_variant	7/13	1		ENSP00000403136
RABGAP1L	ENST00000251507.8	c.929A>G	p.Glu310Gly	missense_variant	7/21	2		ENSP00000251507	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000468 Hom.: 0

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 20, 2023

The c.929A>G (p.E310G) alteration is located in exon 1 (coding exon 1) of the RABGAP1L gene. This alteration results from a A to G substitution at nucleotide position 929, causing the glutamic acid (E) at amino acid position 310 to be replaced by a glycine (G). 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	Benign	0.17
BayesDel_addAF	Benign	-0.013	T
BayesDel_noAF	Benign	-0.26
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.19	.;T;.
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Benign	0.027	D
MetaRNN	Uncertain	0.63	D;D;D
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	1.9	.;L;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-4.0	D;D;D
REVEL	Uncertain	0.39
Sift	Uncertain	0.0070	D;D;D
Sift4G	Uncertain	0.024	D;D;D
Polyphen		0.99	D;P;.
Vest4		0.51
MutPred		0.62		.;Gain of MoRF binding (P = 0.0264);.;
MVP		0.74
MPC		0.89
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.32
gMVP		0.39

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

LitVar

Other links and lift over

dbSNP: rs1672796187; hg19: chr1-174221671;