7-38726932-C-T

Variant names:

• chr7-38726932-C-T
• NM_014396.4:c.2461G>A

Variant summary

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

The NM_014396.4(VPS41):​c.2461G>A​(p.Glu821Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: VPS41 NM_014396.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.57

Genes affected

VPS41 (HGNC:12713): (VPS41 subunit of HOPS complex) Vesicle mediated protein sorting plays an important role in segregation of intracellular molecules into distinct organelles. Genetic studies in yeast have identified more than 40 vacuolar protein sorting (VPS) genes involved in vesicle transport to vacuoles. This gene encodes the human ortholog of yeast Vps41 protein which is also conserved in Drosophila, tomato, and Arabidopsis. Expression studies in yeast and human indicate that this protein may be involved in the formation and fusion of transport vesicles from the Golgi. Several transcript variants encoding different isoforms have been described for this gene, however, the full-length nature of not all is known. [provided by RefSeq, Jul 2008]

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 rank	MANE	Protein	UniProt
VPS41	NM_014396.4	c.2461G>A	p.Glu821Lys	missense_variant	Exon 28 of 29	ENST00000310301.9	NP_055211.2
VPS41	NM_080631.4	c.2386G>A	p.Glu796Lys	missense_variant	Exon 27 of 28		NP_542198.2
VPS41	XM_017011988.2	c.1306G>A	p.Glu436Lys	missense_variant	Exon 15 of 16		XP_016867477.1
VPS41	XR_007060008.1	n.2572G>A		non_coding_transcript_exon_variant	Exon 29 of 29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VPS41	ENST00000310301.9	c.2461G>A	p.Glu821Lys	missense_variant	Exon 28 of 29	1	NM_014396.4	ENSP00000309457.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Nov 26, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2461G>A (p.E821K) alteration is located in exon 28 (coding exon 28) of the VPS41 gene. This alteration results from a G to A substitution at nucleotide position 2461, causing the glutamic acid (E) at amino acid position 821 to be replaced by a lysine (K). 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	0.17
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.030
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.035	T;.
Eigen	Benign	0.15
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Benign	0.024	T
MetaRNN	Uncertain	0.58	D;D
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.8	L;.
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.7	N;N
REVEL	Benign	0.24
Sift	Benign	0.27	T;T
Sift4G	Uncertain	0.035	D;D
Polyphen		0.65	P;.
Vest4		0.77
MutPred		0.28		Gain of methylation at E821 (P = 8e-04);.;
MVP		0.69
MPC		0.49
ClinPred		0.90	D
GERP RS		5.5
Varity_R		0.21
gMVP		0.56

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-38766532;