22-23158939-C-T

Variant names:

• chr22-23158939-C-T
• rs1569215910
• NM_004914.5:c.488C>T

Variant summary

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

The NM_004914.5(RAB36):​c.488C>T​(p.Ser163Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,874 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: RAB36 NM_004914.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.38

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:13437): (radial spoke head 14 homolog) This gene encodes a protein with no known function but with slight similarity to a yeast vacuolar protein. The gene is located in a region deleted in pediatric rhabdoid tumors of the brain, kidney and soft tissues, but mutations in this gene have not been associated with the disease. [provided by RefSeq, Jul 2008]

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 rank	MANE	Protein	UniProt
RAB36	NM_004914.5	c.488C>T	p.Ser163Phe	missense_variant	Exon 8 of 11	ENST00000263116.8	NP_004905.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAB36	ENST00000263116.8	c.488C>T	p.Ser163Phe	missense_variant	Exon 8 of 11	1	NM_004914.5	ENSP00000263116.3
RAB36	ENST00000341989.9	c.422C>T	p.Ser141Phe	missense_variant	Exon 7 of 10	1		ENSP00000343494.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461874 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727240

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 13, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.686C>T (p.S229F) alteration is located in exon 8 (coding exon 8) of the RAB36 gene. This alteration results from a C to T substitution at nucleotide position 686, causing the serine (S) at amino acid position 229 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	Benign	0.14
BayesDel_addAF	Uncertain	0.043	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T;.
Eigen	Benign	0.14
Eigen_PC	Benign	0.095
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Uncertain	0.090	D
MetaRNN	Uncertain	0.70	D;D
MetaSVM	Uncertain	0.11	D
MutationAssessor	Benign	1.5	L;.
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-3.9	D;D
REVEL	Uncertain	0.45
Sift	Uncertain	0.0080	D;D
Sift4G	Uncertain	0.0070	D;D
Polyphen		0.83	P;D
Vest4		0.51
MutPred		0.50		Loss of glycosylation at S229 (P = 0.052);.;
MVP		0.93
MPC		1.3
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.35
gMVP		0.35

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: rs1569215910; hg19: chr22-23501126;