X-70282348-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001363807.1(RAB41):c.124+7G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000604 in 1,209,260 control chromosomes in the GnomAD database, including 1 homozygotes. There are 18 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000099 (0 hom., 1 hem., cov: 23)
  • Exomes 𝑓: 0.000056 (1 hom. 17 hem.)
• Consequence: RAB41 NM_001363807.1 splice_region, intron
• Scores: Splicing: ADA: 0.00009066
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0970

Genes affected

RAB41 (HGNC:18293): (RAB41, member RAS oncogene family) This gene encodes a small GTP-binding protein that belongs to the largest family within the Ras superfamily. These proteins function as regulators of membrane trafficking. They cycle between inactive GDP-bound and activated GTP-bound states, which is controlled by GTP hydrolysis-activating proteins (GAPs). This family member can be activated by the GAP protein RN-Tre, and it is localized to the Golgi complex. [provided by RefSeq, May 2010]

PDZD11 (HGNC:28034): (PDZ domain containing 11) Enables protein C-terminus binding activity. Involved in pore complex assembly. Located in basolateral plasma membrane and cytosol. Part of pore complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant X-70282348-G-A is Benign according to our data. Variant chrX-70282348-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2660811.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Hemizygotes in GnomAdExome at 6 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAB41	NM_001363807.1	c.124+7G>A		splice_region_variant, intron_variant		ENST00000374473.6
RAB41	NM_001032726.3	c.124+7G>A		splice_region_variant, intron_variant
RAB41	XM_011530948.4	c.124+7G>A		splice_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAB41	ENST00000374473.6	c.124+7G>A		splice_region_variant, intron_variant		5	NM_001363807.1	P1
RAB41	ENST00000276066.4	c.124+7G>A		splice_region_variant, intron_variant		1
RAB41	ENST00000509895.5	c.-214G>A		5_prime_UTR_variant	1/3	4
PDZD11	ENST00000695560.1	c.*97-73C>T		intron_variant, NMD_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0000985 AC: 11 AN: 111675 Hom.: 0 Cov.: 23 AF XY: 0.0000295 AC XY: 1 AN XY: 33915

Gnomad AFR AF: 0.0000327

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000283

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000492

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000754

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000109 AC: 20 AN: 183146 Hom.: 0 AF XY: 0.0000888 AC XY: 6 AN XY: 67598

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000730

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000627

Gnomad NFE exome AF: 0.0000857

Gnomad OTH exome AF: 0.000221

GnomAD4 exome AF: 0.0000565 AC: 62 AN: 1097585 Hom.: 1 Cov.: 33 AF XY: 0.0000468 AC XY: 17 AN XY: 362949

Gnomad4 AFR exome AF: 0.0000758

Gnomad4 AMR exome AF: 0.0000852

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000592

Gnomad4 NFE exome AF: 0.0000380

Gnomad4 OTH exome AF: 0.0000217

GnomAD4 genome AF: 0.0000985 AC: 11 AN: 111675 Hom.: 0 Cov.: 23 AF XY: 0.0000295 AC XY: 1 AN XY: 33915

Gnomad4 AFR AF: 0.0000327

Gnomad4 AMR AF: 0.000283

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000492

Gnomad4 NFE AF: 0.0000754

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000868 Hom.: 0

Bravo AF: 0.0000945

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Feb 01, 2023

RAB41: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	0.70
Dann	Benign	0.51

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000091
dbscSNV1_RF	Benign	0.0060
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: rs371005848; hg19: chrX-69502198;