rs2083072989

Variant names:

• chr19-40783792-G-A
• rs2083072989
• NM_016154.5:c.227G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-40783792-G-A
• chr19-40783792-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_016154.5(RAB4B):​c.227G>A​(p.Ser76Asn) 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: 30)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RAB4B NM_016154.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.86
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016154.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAB4B	NM_016154.5	MANE Select	c.227G>A	p.Ser76Asn	missense	Exon 4 of 8	NP_057238.3
	MIA-RAB4B	NR_037775.1		n.589G>A		non_coding_transcript_exon	Exon 6 of 10
	RAB4B-EGLN2	NR_037791.1		n.384G>A		non_coding_transcript_exon	Exon 4 of 12

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAB4B	ENST00000357052.8	TSL:1 MANE Select	c.227G>A	p.Ser76Asn	missense	Exon 4 of 8	ENSP00000349560.2	P61018-1
	RAB4B	ENST00000378307.9	TSL:1	n.227G>A		non_coding_transcript_exon	Exon 4 of 7	ENSP00000367557.4	F6SQB9
	RAB4B-EGLN2	ENST00000594136.2	TSL:2	n.227G>A		non_coding_transcript_exon	Exon 4 of 12	ENSP00000469872.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1266978 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 623844

African (AFR) AF: 0.00 AC: 0 AN: 27972

American (AMR) AF: 0.00 AC: 0 AN: 36254

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18260

East Asian (EAS) AF: 0.00 AC: 0 AN: 26100

South Asian (SAS) AF: 0.00 AC: 0 AN: 80420

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36872

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3510

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 989568

Other (OTH) AF: 0.00 AC: 0 AN: 48022

GnomAD4 genome Cov.: 30

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Uncertain	0.030	T
BayesDel_noAF	Benign	-0.19
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.39	T
Eigen	Benign	0.16
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.10	D
MetaRNN	Uncertain	0.68	D
MetaSVM	Benign	-0.30	T
MutationAssessor	Benign	1.5	L
PhyloP100		7.9
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.55
Sift	Benign	0.084	T
Sift4G	Uncertain	0.043	D
Polyphen		0.029	B
Vest4		0.81
MutPred		0.75		Loss of phosphorylation at S76 (P = 0.0594)
MVP		0.68
MPC		0.32
ClinPred		0.95	D
GERP RS		4.8
Varity_R		0.48
gMVP		0.64
Mutation Taster		=21/79	disease causing

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

Other links and lift over

dbSNP: rs2083072989; hg19: chr19-41289697;