X-70284024-C-T

Position:

• chrX-70284024-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001363807.1(RAB41):​c.530C>T​(p.Thr177Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 22)
• Consequence: RAB41 NM_001363807.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.33

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAB41	NM_001363807.1	c.530C>T	p.Thr177Ile	missense_variant	6/8	ENST00000374473.6	NP_001350736.1
RAB41	NM_001032726.3	c.527C>T	p.Thr176Ile	missense_variant	6/8		NP_001027898.2
RAB41	XM_011530948.4	c.530C>T	p.Thr177Ile	missense_variant	6/7		XP_011529250.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAB41	ENST00000374473.6	c.530C>T	p.Thr177Ile	missense_variant	6/8	5	NM_001363807.1	ENSP00000363597.2
RAB41	ENST00000276066.4	c.527C>T	p.Thr176Ile	missense_variant	6/8	1		ENSP00000276066.4
PDZD11	ENST00000695560.1	n.*97-1749G>A		intron_variant				ENSP00000512017.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 09, 2024

The c.527C>T (p.T176I) alteration is located in exon 6 (coding exon 6) of the RAB41 gene. This alteration results from a C to T substitution at nucleotide position 527, causing the threonine (T) at amino acid position 176 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Uncertain	0.027	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.42	T;.
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Benign	0.016	T
MetaRNN	Uncertain	0.47	T;T
MetaSVM	Uncertain	-0.076	T
MutationAssessor	Pathogenic	3.1	M;.
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.1	N;N
REVEL	Uncertain	0.34
Sift	Uncertain	0.0060	D;D
Sift4G	Uncertain	0.030	D;D
Polyphen		0.99	D;D
Vest4		0.36
MutPred		0.56		Gain of catalytic residue at T177 (P = 0.0157);.;
MVP		0.95
MPC		0.51
ClinPred		0.92	D
GERP RS		1.9
Varity_R		0.090
gMVP		0.75

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-69503874;