chr19-40783965-G-C

Variant names:

• chr19-40783965-G-C
• NM_016154.5:c.320G>C

Variant summary

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

The NM_016154.5(RAB4B):​c.320G>C​(p.Arg107Pro) 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. 12/21 in silico tools predict a damaging outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 31)
• Consequence: RAB4B NM_016154.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.95

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 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, 0.944

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAB4B	NM_016154.5	c.320G>C	p.Arg107Pro	missense_variant	Exon 5 of 8	ENST00000357052.8	NP_057238.3
MIA-RAB4B	NR_037775.1	n.682G>C		non_coding_transcript_exon_variant	Exon 7 of 10
RAB4B-EGLN2	NR_037791.1	n.477G>C		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.320G>C	p.Arg107Pro	missense_variant	Exon 5 of 8	1	NM_016154.5	ENSP00000349560.2
RAB4B-EGLN2	ENST00000594136.2	n.320G>C		non_coding_transcript_exon_variant	Exon 5 of 12	2		ENSP00000469872.1
MIA-RAB4B	ENST00000600729.2	n.*280G>C		non_coding_transcript_exon_variant	Exon 8 of 11	5		ENSP00000472384.1
MIA-RAB4B	ENST00000600729.2	n.*280G>C		3_prime_UTR_variant	Exon 8 of 11	5		ENSP00000472384.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.63	D;D
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.98	.;D
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.94	D;D
MetaSVM	Uncertain	0.47	D
MutationAssessor	Pathogenic	3.5	H;H
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-6.1	.;D
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	.;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;D
Vest4		0.96
MutPred		0.72		Gain of glycosylation at T108 (P = 0.1348);Gain of glycosylation at T108 (P = 0.1348);
MVP		0.94
MPC		0.61
ClinPred		1.0	D
GERP RS		3.9
Varity_R		0.94
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: chr19-41289870;