22-23160923-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_004914.5(RAB36):c.664T>C(p.Phe222Leu) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: RAB36 NM_004914.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.21

Genes affected

RAB36 (HGNC:9775): (RAB36, member RAS oncogene family) Predicted to enable GTP binding activity and GTPase activity. Predicted to be involved in protein transport. Predicted to be located in Golgi membrane. [provided by Alliance of Genome Resources, Apr 2022]

RSPH14 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.85

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAB36	NM_004914.5	c.664T>C	p.Phe222Leu	missense_variant	10/11	ENST00000263116.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAB36	ENST00000263116.8	c.664T>C	p.Phe222Leu	missense_variant	10/11	1	NM_004914.5	P1
RAB36	ENST00000341989.9	c.598T>C	p.Phe200Leu	missense_variant	9/10	1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 40

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

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 04, 2022

The c.862T>C (p.F288L) alteration is located in exon 10 (coding exon 10) of the RAB36 gene. This alteration results from a T to C substitution at nucleotide position 862, causing the phenylalanine (F) at amino acid position 288 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	0.97
BayesDel_addAF	Uncertain	0.063	T
BayesDel_noAF	Benign	-0.15
Cadd	Uncertain	26
Dann	Uncertain	1.0
DEOGEN2	Benign	0.13	T;.
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.85	D;D
MetaSVM	Uncertain	0.012	D
MutationAssessor	Benign	0.86	L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-5.7	D;D
REVEL	Uncertain	0.56
Sift	Benign	0.044	D;D
Sift4G	Benign	0.067	T;D
Polyphen		0.99	D;D
Vest4		0.72
MutPred		0.43		Gain of disorder (P = 0.1129);.;
MVP		0.95
MPC		1.4
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.60
gMVP		0.62

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

Publications

LitVar

Other links and lift over

dbSNP: rs895334407; hg19: chr22-23503110;