X-70284588-CG-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 2P and 10B. PVS1_Moderate BP6_Moderate BS1 BS2

The NM_001363807.1(RAB41):c.616del(p.Val206LeufsTer27) variant causes a frameshift, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.001 in 1,206,360 control chromosomes in the GnomAD database, including 7 homozygotes. There are 305 hemizygotes in GnomAD. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0057 (6 hom., 168 hem., cov: 22)
  • Exomes 𝑓: 0.00053 (1 hom. 137 hem.)
• Consequence: RAB41 NM_001363807.1 frameshift, splice_region
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.127

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 -8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0807 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• BP6: Variant X-70284588-CG-C is Benign according to our data. Variant chrX-70284588-CG-C is described in ClinVar as [Benign]. Clinvar id is 714927.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00568 (634/111697) while in subpopulation AFR AF= 0.0192 (590/30715). AF 95% confidence interval is 0.0179. There are 6 homozygotes in gnomad4. There are 168 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 6 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAB41	NM_001363807.1	c.616del	p.Val206LeufsTer27	frameshift_variant, splice_region_variant	8/8	ENST00000374473.6
RAB41	NM_001032726.3	c.613del	p.Val205LeufsTer27	frameshift_variant, splice_region_variant	8/8
RAB41	XM_011530948.4	c.*154del		3_prime_UTR_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAB41	ENST00000374473.6	c.616del	p.Val206LeufsTer27	frameshift_variant, splice_region_variant	8/8	5	NM_001363807.1	P1
RAB41	ENST00000276066.4	c.613del	p.Val205LeufsTer27	frameshift_variant, splice_region_variant	8/8	1
PDZD11	ENST00000695561.1	n.3337del		non_coding_transcript_exon_variant	6/6
PDZD11	ENST00000695560.1	c.*97-2314del		intron_variant, NMD_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00568 AC: 634 AN: 111644 Hom.: 6 Cov.: 22 AF XY: 0.00497 AC XY: 168 AN XY: 33836

Gnomad AFR AF: 0.0193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00305

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000375

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000752

Gnomad OTH AF: 0.00469

GnomAD3 exomes AF: 0.00168 AC: 308 AN: 183392 Hom.: 3 AF XY: 0.000885 AC XY: 60 AN XY: 67832

Gnomad AFR exome AF: 0.0210

Gnomad AMR exome AF: 0.000802

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000366

Gnomad OTH exome AF: 0.00155

GnomAD4 exome AF: 0.000525 AC: 575 AN: 1094663 Hom.: 1 Cov.: 29 AF XY: 0.000380 AC XY: 137 AN XY: 360165

Gnomad4 AFR exome AF: 0.0185

Gnomad4 AMR exome AF: 0.000767

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000185

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000834

Gnomad4 OTH exome AF: 0.00104

GnomAD4 genome AF: 0.00568 AC: 634 AN: 111697 Hom.: 6 Cov.: 22 AF XY: 0.00496 AC XY: 168 AN XY: 33897

Gnomad4 AFR AF: 0.0192

Gnomad4 AMR AF: 0.00304

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000376

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000753

Gnomad4 OTH AF: 0.00464

Alfa AF: 0.000882 Hom.: 16

Bravo AF: 0.00654

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

May 03, 2018

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Computational scores

Source: dbNSFP v4.3

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: rs773970714; hg19: chrX-69504438;