X-70284271-C-G

Variant names:

• chrX-70284271-C-G
• rs1361304714
• NM_001363807.1:c.555C>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001363807.1(RAB41):​c.555C>G​(p.Phe185Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000333 in 1,201,525 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000029 (0 hom., 1 hem., cov: 20)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: RAB41 NM_001363807.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.723
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.907

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001363807.1. 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
	RAB41	NM_001363807.1	MANE Select	c.555C>G	p.Phe185Leu	missense	Exon 7 of 8	NP_001350736.1	Q5JT25-1
	RAB41	NM_001032726.3		c.552C>G	p.Phe184Leu	missense	Exon 7 of 8	NP_001027898.2	Q5JT25-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAB41	ENST00000374473.6	TSL:5 MANE Select	c.555C>G	p.Phe185Leu	missense	Exon 7 of 8	ENSP00000363597.2	Q5JT25-1
	RAB41	ENST00000276066.4	TSL:1	c.552C>G	p.Phe184Leu	missense	Exon 7 of 8	ENSP00000276066.4	Q5JT25-2
	PDZD11	ENST00000695561.1		n.3655G>C		non_coding_transcript_exon	Exon 6 of 6

Frequencies

GnomAD3 genomes AF: 0.0000286 AC: 3 AN: 105045 Hom.: 0 Cov.: 20

Gnomad AFR AF: 0.000105

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 9.12e-7 AC: 1 AN: 1096480 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 361922

African (AFR) AF: 0.00 AC: 0 AN: 26349

American (AMR) AF: 0.00 AC: 0 AN: 35120

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19358

East Asian (EAS) AF: 0.00 AC: 0 AN: 30192

South Asian (SAS) AF: 0.00 AC: 0 AN: 53928

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40511

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4099

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 840890

Other (OTH) AF: 0.00 AC: 0 AN: 46033

GnomAD4 genome AF: 0.0000286 AC: 3 AN: 105045 Hom.: 0 Cov.: 20 AF XY: 0.0000356 AC XY: 1 AN XY: 28125

African (AFR) AF: 0.000105 AC: 3 AN: 28449

American (AMR) AF: 0.00 AC: 0 AN: 9681

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2567

East Asian (EAS) AF: 0.00 AC: 0 AN: 3336

South Asian (SAS) AF: 0.00 AC: 0 AN: 2221

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4998

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 226

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 51513

Other (OTH) AF: 0.00 AC: 0 AN: 1389

Alfa AF: 0.00 Hom.: 1

Bravo AF: 0.0000151

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Uncertain	0.032	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	16
DANN	Benign	0.97
DEOGEN2	Uncertain	0.61	D
FATHMM_MKL	Benign	0.28	N
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.041	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		0.72
PrimateAI	Benign	0.45	T
PROVEAN	Pathogenic	-5.5	D
REVEL	Uncertain	0.34
Sift	Uncertain	0.017	D
Sift4G	Uncertain	0.0070	D
Polyphen		1.0	D
Vest4		0.45
MutPred		0.89		Loss of methylation at K183 (P = 0.0887)
MVP		0.87
MPC		0.65
ClinPred		1.0	D
GERP RS		-1.4
Varity_R		0.39
gMVP		0.91
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1361304714; hg19: chrX-69504121;