chr14-64951099-A-G

Position:

• chr14-64951099-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001308154.2(RAB15):​c.299T>C​(p.Met100Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,460,770 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: RAB15 NM_001308154.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.45

Genes affected

RAB15 (HGNC:20150): (RAB15, member RAS oncogene family) Predicted to enable GTP binding activity and GTPase activity. Involved in positive regulation of regulated secretory pathway. Located in cilium; endosome membrane; and perinuclear region of cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

CHURC1-FNTB (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33624256).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAB15	NM_001308154.2	c.299T>C	p.Met100Thr	missense_variant	4/7	ENST00000533601.7	NP_001295083.1
CHURC1-FNTB	NM_001202559.1	c.327+25019A>G		intron_variant			NP_001189488.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAB15	ENST00000533601.7	c.299T>C	p.Met100Thr	missense_variant	4/7	1	NM_001308154.2	ENSP00000434103	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1460770 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 726790

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: 0.00000360

Gnomad4 OTH exome AF: 0.00

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

May 17, 2023

The c.299T>C (p.M100T) alteration is located in exon 4 (coding exon 4) of the RAB15 gene. This alteration results from a T to C substitution at nucleotide position 299, causing the methionine (M) at amino acid position 100 to be replaced by a threonine (T). 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	Benign	0.27
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Benign	22
DANN	Benign	0.95
DEOGEN2	Benign	0.16	.;T;T;.;.;.
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.92	D;T;T;T;T;D
M_CAP	Benign	0.080	D
MetaRNN	Benign	0.34	T;T;T;T;T;T
MetaSVM	Benign	-0.45	T
MutationAssessor	Benign	-1.1	N;N;.;.;.;.
MutationTaster	Benign	1.0	D;D;N;N;N;N
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.27	N;N;N;.;.;.
REVEL	Uncertain	0.40
Sift	Benign	0.096	T;T;T;.;.;.
Sift4G	Benign	0.14	T;T;.;.;.;.
Polyphen		0.99	D;.;.;.;.;.
Vest4		0.54
MutPred		0.32		Loss of stability (P = 0.0397);Loss of stability (P = 0.0397);.;.;.;.;
MVP		0.93
MPC		0.86
ClinPred		0.87	D
GERP RS		5.6
Varity_R		0.15
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: chr14-65417817;