chrX-155259724-T-G

Variant names:

• chrX-155259724-T-G
• rs147409916
• NM_171998.4:c.*1079A>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_171998.4(RAB39B):​c.*1079A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000729 in 112,450 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 31 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00073 (0 hom., 31 hem., cov: 23)
  • Failed GnomAD Quality Control
• Consequence: RAB39B NM_171998.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.199
• Publications: 0 publications found

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]

RAB39B Gene-Disease associations (from GenCC):

• early-onset parkinsonism-intellectual disability syndrome

  Inheritance: XL Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
• intellectual disability, X-linked 72

  Inheritance: XL Classification: DEFINITIVE, MODERATE Submitted by: Ambry Genetics, G2P
• non-syndromic X-linked intellectual disability

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant X-155259724-T-G is Benign according to our data. Variant chrX-155259724-T-G is described in ClinVar as Benign. ClinVar VariationId is 368138.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000729 (82/112450) while in subpopulation EAS AF = 0.0214 (77/3590). AF 95% confidence interval is 0.0176. There are 0 homozygotes in GnomAd4. There are 31 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 31 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_171998.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAB39B	NM_171998.4	MANE Select	c.*1079A>C		3_prime_UTR	Exon 2 of 2	NP_741995.1	Q96DA2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAB39B	ENST00000369454.4	TSL:1 MANE Select	c.*1079A>C		3_prime_UTR	Exon 2 of 2	ENSP00000358466.3	Q96DA2

Frequencies

GnomAD3 genomes AF: 0.000730 AC: 82 AN: 112398 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000940

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0214

Gnomad SAS AF: 0.000369

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000375

Gnomad OTH AF: 0.000662

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

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.000729 AC: 82 AN: 112450 Hom.: 0 Cov.: 23 AF XY: 0.000896 AC XY: 31 AN XY: 34610

African (AFR) AF: 0.00 AC: 0 AN: 30988

American (AMR) AF: 0.0000939 AC: 1 AN: 10648

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2648

East Asian (EAS) AF: 0.0214 AC: 77 AN: 3590

South Asian (SAS) AF: 0.000370 AC: 1 AN: 2705

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6123

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.0000375 AC: 2 AN: 53313

Other (OTH) AF: 0.000654 AC: 1 AN: 1528

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00148

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Intellectual disability, X-linked 72 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.65
DANN	Benign	0.78
PhyloP100		-0.20
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs147409916; hg19: chrX-154489009;