chr3-19975627-C-T

Position:

• chr3-19975627-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_004162.5(RAB5A):​c.190C>T​(p.Leu64Phe) variant causes a missense change involving the alteration of a non-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: 32)
• Consequence: RAB5A NM_004162.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.16

Genes affected

RAB5A (HGNC:9783): (RAB5A, member RAS oncogene family) Enables GDP binding activity; GTP binding activity; and GTPase activity. Involved in several processes, including amyloid-beta clearance by transcytosis; early endosome to late endosome transport; and regulation of exocytosis. Located in several cellular components, including cytoplasmic side of early endosome membrane; nucleoplasm; and terminal bouton. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAB5A	NM_004162.5	c.190C>T	p.Leu64Phe	missense_variant	3/6	ENST00000273047.9
RAB5A	XM_047448648.1	c.-72C>T		5_prime_UTR_variant	3/6
RAB5A	NM_001292048.2	c.164-16C>T		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAB5A	ENST00000273047.9	c.190C>T	p.Leu64Phe	missense_variant	3/6	1	NM_004162.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

Mar 07, 2023

The c.190C>T (p.L64F) alteration is located in exon 3 (coding exon 2) of the RAB5A gene. This alteration results from a C to T substitution at nucleotide position 190, causing the leucine (L) at amino acid position 64 to be replaced by a phenylalanine (F). 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	0.67
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.030
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.74	D
Eigen	Benign	0.14
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.040	D
MetaRNN	Uncertain	0.56	D
MetaSVM	Benign	-0.49	T
MutationAssessor	Benign	1.4	L
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.42
Sift	Uncertain	0.016	D
Sift4G	Uncertain	0.036	D
Polyphen		0.23	B
Vest4		0.68
MutPred		0.56		Gain of sheet (P = 0.1539);
MVP		0.81
MPC		0.67
ClinPred		0.92	D
GERP RS		5.2
Varity_R		0.73
gMVP		0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.23		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.23		Position offset: 16

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: chr3-20017119;