X-70284614-G-C

Position:

• chrX-70284614-G-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001363807.1(RAB41):​c.640G>C​(p.Glu214Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: RAB41 NM_001363807.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.265

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:):

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.050843984).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAB41	NM_001363807.1	c.640G>C	p.Glu214Gln	missense_variant	8/8	ENST00000374473.6	NP_001350736.1
RAB41	NM_001032726.3	c.637G>C	p.Glu213Gln	missense_variant	8/8		NP_001027898.2
RAB41	XM_011530948.4	c.*178G>C		3_prime_UTR_variant	7/7		XP_011529250.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAB41	ENST00000374473.6	c.640G>C	p.Glu214Gln	missense_variant	8/8	5	NM_001363807.1	ENSP00000363597.2
RAB41	ENST00000276066.4	c.637G>C	p.Glu213Gln	missense_variant	8/8	1		ENSP00000276066.4
PDZD11	ENST00000695561.1	n.3312C>G		non_coding_transcript_exon_variant	6/6
PDZD11	ENST00000695560.1	n.*97-2339C>G		intron_variant				ENSP00000512017.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 29

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

May 17, 2023

The c.637G>C (p.E213Q) alteration is located in exon 8 (coding exon 8) of the RAB41 gene. This alteration results from a G to C substitution at nucleotide position 637, causing the glutamic acid (E) at amino acid position 213 to be replaced by a glutamine (Q). 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	Benign	0.085
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.031
DANN	Benign	0.64
DEOGEN2	Benign	0.021	T;.
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.45	T;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.051	T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.41	N;.
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.020	N;N
REVEL	Benign	0.051
Sift	Benign	0.69	T;T
Sift4G	Benign	0.83	T;T
Polyphen		0.047	B;B
Vest4		0.063
MutPred		0.14		Loss of glycosylation at S216 (P = 0.1298);.;
MVP		0.44
MPC		0.15
ClinPred		0.078	T
GERP RS		-4.8
Varity_R		0.058
gMVP		0.59

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-69504464;