7-66783735-A-T

Position:

• chr7-66783735-A-T

Variant summary

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

The NM_014504.3(RABGEF1):​c.407A>T​(p.Asp136Val) 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: RABGEF1 NM_014504.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.43

Genes affected

RABGEF1 (HGNC:17676): (RAB guanine nucleotide exchange factor 1) RABGEF1 forms a complex with rabaptin-5 (RABPT5; MIM 603616) that is required for endocytic membrane fusion, and it serves as a specific guanine nucleotide exchange factor (GEF) for RAB5 (RAB5A; MIM 179512) (Horiuchi et al., 1997 [PubMed 9323142]).[supplied by OMIM, Mar 2010]

ENSG00000284461 (HGNC:):

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
RABGEF1	NM_014504.3	c.407A>T	p.Asp136Val	missense_variant	4/9	ENST00000284957.9	NP_055319.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RABGEF1	ENST00000284957.9	c.407A>T	p.Asp136Val	missense_variant	4/9	1	NM_014504.3	ENSP00000284957.4
ENSG00000284461	ENST00000503687.2	n.*242A>T		non_coding_transcript_exon_variant	7/13	2		ENSP00000421074.1
ENSG00000284461	ENST00000503687.2	n.*242A>T		3_prime_UTR_variant	7/13	2		ENSP00000421074.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

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

Jun 22, 2021

The c.407A>T (p.D136V) alteration is located in exon 4 (coding exon 3) of the RABGEF1 gene. This alteration results from a A to T substitution at nucleotide position 407, causing the aspartic acid (D) at amino acid position 136 to be replaced by a valine (V). 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	0.49
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.067	.;.;.;T
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.96	.;D;D;D
M_CAP	Benign	0.036	D
MetaRNN	Uncertain	0.69	D;D;D;D
MetaSVM	Benign	-1.1	T
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-3.2	D;D;.;D
REVEL	Uncertain	0.52
Sift	Uncertain	0.017	D;D;.;D
Sift4G	Uncertain	0.033	D;D;T;T
Vest4		0.81
MVP		0.46
MPC		0.45
ClinPred		0.95	D
GERP RS		5.6
gMVP		0.62

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: chr7-66248722;