X-155259456-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_171998.4(RAB39B):c.*1347C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.041 in 111,424 control chromosomes in the GnomAD database, including 102 homozygotes. There are 1,313 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.041 (102 hom., 1313 hem., cov: 23)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: RAB39B NM_171998.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.139

Genes affected

RAB39B (HGNC:16499): (RAB39B, member RAS oncogene family) This gene encodes a member of the Rab family of proteins. Rab proteins are small GTPases that are involved in vesicular trafficking. Mutations in this gene are associated with X-linked cognitive disability. [provided by RefSeq, Aug 2013]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant X-155259456-G-A is Benign according to our data. Variant chrX-155259456-G-A is described in ClinVar as [Benign]. Clinvar id is 368137.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-155259456-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0707 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAB39B	NM_171998.4	c.*1347C>T		3_prime_UTR_variant	2/2	ENST00000369454.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAB39B	ENST00000369454.4	c.*1347C>T		3_prime_UTR_variant	2/2	1	NM_171998.4	P1

Frequencies

GnomAD3 genomes AF: 0.0410 AC: 4569 AN: 111367 Hom.: 102 Cov.: 23 AF XY: 0.0390 AC XY: 1309 AN XY: 33583

Gnomad AFR AF: 0.0732

Gnomad AMI AF: 0.0204

Gnomad AMR AF: 0.0152

Gnomad ASJ AF: 0.0230

Gnomad EAS AF: 0.00141

Gnomad SAS AF: 0.0424

Gnomad FIN AF: 0.0189

Gnomad MID AF: 0.00840

Gnomad NFE AF: 0.0343

Gnomad OTH AF: 0.0306

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 6 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 4

Gnomad4 NFE exome AF: 0.00

GnomAD4 genome AF: 0.0410 AC: 4573 AN: 111424 Hom.: 102 Cov.: 23 AF XY: 0.0390 AC XY: 1313 AN XY: 33650

Gnomad4 AFR AF: 0.0732

Gnomad4 AMR AF: 0.0152

Gnomad4 ASJ AF: 0.0230

Gnomad4 EAS AF: 0.00141

Gnomad4 SAS AF: 0.0424

Gnomad4 FIN AF: 0.0189

Gnomad4 NFE AF: 0.0343

Gnomad4 OTH AF: 0.0302

Alfa AF: 0.0419 Hom.: 563

Bravo AF: 0.0413

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Intellectual disability, X-linked 72 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
Cadd	Benign	1.5
Dann	Benign	0.80

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: rs17052027; hg19: chrX-154488741;