chr19-40784057-C-A

Variant names:

• chr19-40784057-C-A
• NM_016154.5:c.412C>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_016154.5(RAB4B):​c.412C>A​(p.Arg138Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,358 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RAB4B NM_016154.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.10

Genes affected

RAB4B (HGNC:9782): (RAB4B, member RAS oncogene family) Predicted to enable G protein activity and GTP binding activity. Involved in glucose import. Located in insulin-responsive compartment; perinuclear region of cytoplasm; and recycling endosome. [provided by Alliance of Genome Resources, Apr 2022]

RAB4B-EGLN2 (HGNC:44465): (RAB4B-EGLN2 readthrough (NMD candidate)) This locus represents naturally occurring read-through transcription between the neighboring RAB4B (RAB4B, member RAS oncogene family) and EGLN2 (egl nine homolog 2) genes on chromosome 19. The read-through transcript is a candidate for nonsense-mediated mRNA decay (NMD), and is thus unlikely to produce a protein product. [provided by RefSeq, Feb 2011]

MIA-RAB4B (HGNC:48352): (MIA-RAB4B readthrough (NMD candidate)) This locus represents naturally occurring read-through transcription between the neighboring MIA (melanoma inhibitory activity) and RAB4B (RAB4B, member RAS oncogene family) genes on chromosome 19. The read-through transcript is a candidate for nonsense-mediated mRNA decay (NMD), and is therefore unlikely to produce a protein product. [provided by RefSeq, Feb 2011]

ENSG00000282951 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.753

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAB4B	NM_016154.5	c.412C>A	p.Arg138Ser	missense_variant	Exon 5 of 8	ENST00000357052.8	NP_057238.3
MIA-RAB4B	NR_037775.1	n.774C>A		non_coding_transcript_exon_variant	Exon 7 of 10
RAB4B-EGLN2	NR_037791.1	n.569C>A		non_coding_transcript_exon_variant	Exon 5 of 12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAB4B	ENST00000357052.8	c.412C>A	p.Arg138Ser	missense_variant	Exon 5 of 8	1	NM_016154.5	ENSP00000349560.2
RAB4B-EGLN2	ENST00000594136.2	n.412C>A		non_coding_transcript_exon_variant	Exon 5 of 12	2		ENSP00000469872.1
MIA-RAB4B	ENST00000600729.2	n.*372C>A		non_coding_transcript_exon_variant	Exon 8 of 11	5		ENSP00000472384.1
MIA-RAB4B	ENST00000600729.2	n.*372C>A		3_prime_UTR_variant	Exon 8 of 11	5		ENSP00000472384.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460358 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 726366

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.54	D;D
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.23
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.95	.;D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.75	D;D
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	-0.080	N;N
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-2.9	.;D
REVEL	Uncertain	0.49
Sift	Benign	0.060	.;T
Sift4G	Benign	0.23	T;T
Polyphen		0.76	P;P
Vest4		0.78
MutPred		0.34		Gain of disorder (P = 0.0652);Gain of disorder (P = 0.0652);
MVP		0.88
MPC		0.40
ClinPred		0.91	D
GERP RS		1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.78
gMVP		0.76

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: chr19-41289962; COSMIC: COSV100826439; COSMIC: COSV100826439;