7-38726320-C-T

Variant names:

• chr7-38726320-C-T
• NM_014396.4:c.2491G>A

Variant summary

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

The NM_014396.4(VPS41):​c.2491G>A​(p.Ala831Thr) 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. 16/21 in silico tools predict a benign outcome for this variant. 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: 0.782

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 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=0.03730002).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VPS41	NM_014396.4	c.2491G>A	p.Ala831Thr	missense_variant	Exon 29 of 29	ENST00000310301.9	NP_055211.2
VPS41	NM_080631.4	c.2416G>A	p.Ala806Thr	missense_variant	Exon 28 of 28		NP_542198.2
VPS41	XM_017011988.2	c.1336G>A	p.Ala446Thr	missense_variant	Exon 16 of 16		XP_016867477.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VPS41	ENST00000310301.9	c.2491G>A	p.Ala831Thr	missense_variant	Exon 29 of 29	1	NM_014396.4	ENSP00000309457.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

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 08, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2491G>A (p.A831T) alteration is located in exon 29 (coding exon 29) of the VPS41 gene. This alteration results from a G to A substitution at nucleotide position 2491, causing the alanine (A) at amino acid position 831 to be replaced by a threonine (T). 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	0.062
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	19
DANN	Benign	0.82
DEOGEN2	Benign	0.0051	T;.
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.75	T;T
M_CAP	Benign	0.0071	T
MetaRNN	Benign	0.037	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.14	N;.
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.61	N;N
REVEL	Benign	0.056
Sift	Benign	0.78	T;T
Sift4G	Benign	0.67	T;T
Polyphen		0.0	B;.
Vest4		0.056
MutPred		0.19		Loss of disorder (P = 0.1529);.;
MVP		0.53
MPC		0.28
ClinPred		0.36	T
GERP RS		2.1
Varity_R		0.046
gMVP		0.30

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: chr7-38765920;