chr19-40780497-T-G

Position:

• chr19-40780497-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PP3_Strong

The NM_016154.5(RAB4B):​c.210T>G​(p.Phe70Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.00044 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RAB4B NM_016154.5 missense, splice_region
• Scores: Splicing: ADA: 0.1050
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.413

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]

MIA-RAB4B (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.944

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAB4B	NM_016154.5	c.210T>G	p.Phe70Leu	missense_variant, splice_region_variant	3/8	ENST00000357052.8	NP_057238.3
MIA-RAB4B	NR_037775.1	n.572T>G		splice_region_variant, non_coding_transcript_exon_variant	5/10
RAB4B-EGLN2	NR_037791.1	n.367T>G		splice_region_variant, non_coding_transcript_exon_variant	3/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAB4B	ENST00000357052.8	c.210T>G	p.Phe70Leu	missense_variant, splice_region_variant	3/8	1	NM_016154.5	ENSP00000349560	P1
	ENST00000595728.2	n.992-606A>C		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000440 AC: 642 AN: 1460414 Hom.: 0 Cov.: 31 AF XY: 0.000423 AC XY: 307 AN XY: 726480

Gnomad4 AFR exome AF: 0.000628

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000139

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000523

Gnomad4 OTH exome AF: 0.000365

GnomAD4 genome Cov.: 30

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

May 30, 2024

The c.210T>G (p.F70L) alteration is located in exon 3 (coding exon 3) of the RAB4B gene. This alteration results from a T to G substitution at nucleotide position 210, causing the phenylalanine (F) at amino acid position 70 to be replaced by a leucine (L). 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	1.0
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.61	D;D
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.22
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.94	.;D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.94	D;D
MetaSVM	Uncertain	0.33	D
MutationAssessor	Pathogenic	3.0	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-5.4	.;D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0030	.;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		0.99	D;D
Vest4		0.86
MutPred		0.85		Gain of disorder (P = 0.1402);Gain of disorder (P = 0.1402);
MVP		0.88
MPC		0.87
ClinPred		0.98	D
GERP RS		2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.92
gMVP		0.78

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.10
dbscSNV1_RF	Benign	0.30
SpliceAI score (max)		0.030		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: chr19-41286402;