1-229288767-G-A

Position:

• chr1-229288767-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_004578.4(RAB4A):​c.151G>A​(p.Gly51Ser) variant causes a missense change involving the alteration of a 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: RAB4A NM_004578.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.72

Genes affected

RAB4A (HGNC:9781): (RAB4A, member RAS oncogene family) This gene is a member of the largest group in the Ras superfamily of small GTPases, which regulate membrane trafficking. The encoded protein is associated with early endosomes and is involved in their sorting and recycling. The protein also plays a role in regulating the recycling of receptors from endosomes to the plasma membrane. Alternatively spliced transcript variants have been observed for this gene. [provided by RefSeq, Dec 2012]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a mutagenesis_site 10-fold decrease in ZFYVE20 binding affinity. (size 0) in uniprot entity RAB4A_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.832

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAB4A	NM_004578.4	c.151G>A	p.Gly51Ser	missense_variant	3/8	ENST00000366690.5
RAB4A	NM_001271998.2	c.-50-7081G>A		intron_variant
RAB4A	NR_073545.2	n.380G>A		non_coding_transcript_exon_variant	3/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAB4A	ENST00000366690.5	c.151G>A	p.Gly51Ser	missense_variant	3/8	1	NM_004578.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 28

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

Jan 25, 2023

The c.151G>A (p.G51S) alteration is located in exon 3 (coding exon 3) of the RAB4A gene. This alteration results from a G to A substitution at nucleotide position 151, causing the glycine (G) at amino acid position 51 to be replaced by a serine (S). 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	0.91
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	0.0
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.55	D
Eigen	Uncertain	0.57
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.049	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Benign	0.62	N
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-2.9	D
REVEL	Uncertain	0.58
Sift	Benign	0.13	T
Sift4G	Benign	0.12	T
Vest4		0.79
MVP		0.86
MPC		1.6
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.71
gMVP		0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		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: chr1-229424514;