rs996238062

Variant names:

• chr1-229297591-C-G
• rs996238062
• NM_004578.4:c.400C>G

Your query was ambiguous. Multiple possible variants found:

• chr1-229297591-C-G
• chr1-229297591-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_004578.4(RAB4A):​c.400C>G​(p.Arg134Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R134C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: RAB4A NM_004578.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.90

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.943

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAB4A	NM_004578.4	c.400C>G	p.Arg134Gly	missense_variant	Exon 5 of 8	ENST00000366690.5	NP_004569.2
RAB4A	NM_001271998.2	c.85C>G	p.Arg29Gly	missense_variant	Exon 3 of 6		NP_001258927.1
RAB4A	NR_073545.2	n.591C>G		non_coding_transcript_exon_variant	Exon 5 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAB4A	ENST00000366690.5	c.400C>G	p.Arg134Gly	missense_variant	Exon 5 of 8	1	NM_004578.4	ENSP00000355651.4
RAB4A	ENST00000618010.4	c.85C>G	p.Arg29Gly	missense_variant	Exon 3 of 6	3		ENSP00000482077.1
RAB4A	ENST00000473894.1	n.350C>G		non_coding_transcript_exon_variant	Exon 3 of 6	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	T;D
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.94	D;D
MetaSVM	Uncertain	0.73	D
MutationAssessor	Pathogenic	3.3	.;M
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-5.0	.;D
REVEL	Pathogenic	0.86
Sift	Benign	0.045	.;D
Sift4G	Benign	0.089	T;D
Vest4		0.92
MVP		0.94
MPC		1.8
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.74
gMVP		0.93

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: rs996238062; hg19: chr1-229433338;