7-38726254-T-C

Variant names:

• chr7-38726254-T-C
• rs201021270
• NM_014396.4:c.2557A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014396.4(VPS41):​c.2557A>G​(p.Lys853Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00000124 in 1,608,454 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: VPS41 NM_014396.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.38
• Publications: 0 publications found

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]

VPS41 Gene-Disease associations (from GenCC):

• spinocerebellar ataxia, autosomal recessive 29

  Inheritance: Unknown, AR Classification: MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• autosomal recessive cerebellar ataxia-saccadic intrusion syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10255891).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014396.4. 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
	VPS41	NM_014396.4	MANE Select	c.2557A>G	p.Lys853Glu	missense	Exon 29 of 29	NP_055211.2	P49754-1
	VPS41	NM_080631.4		c.2482A>G	p.Lys828Glu	missense	Exon 28 of 28	NP_542198.2	P49754-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS41	ENST00000310301.9	TSL:1 MANE Select	c.2557A>G	p.Lys853Glu	missense	Exon 29 of 29	ENSP00000309457.4	P49754-1
	VPS41	ENST00000448833.5	TSL:1	n.*242A>G		non_coding_transcript_exon	Exon 8 of 8	ENSP00000391980.1	H7BZX6
	VPS41	ENST00000448833.5	TSL:1	n.*242A>G		3_prime_UTR	Exon 8 of 8	ENSP00000391980.1	H7BZX6

Frequencies

GnomAD3 genomes AF: 0.00000659 AC: 1 AN: 151816 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000403 AC: 1 AN: 248226 AF XY: 0.00000744

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000899

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1456520 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 724784

African (AFR) AF: 0.00 AC: 0 AN: 33438

American (AMR) AF: 0.00 AC: 0 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26106

East Asian (EAS) AF: 0.00 AC: 0 AN: 39670

South Asian (SAS) AF: 0.00 AC: 0 AN: 86150

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52812

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 9.03e-7 AC: 1 AN: 1107680

Other (OTH) AF: 0.00 AC: 0 AN: 60216

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151934 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74236

African (AFR) AF: 0.00 AC: 0 AN: 41546

American (AMR) AF: 0.00 AC: 0 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67894

Other (OTH) AF: 0.00 AC: 0 AN: 2108

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.021	T
Eigen	Benign	-0.064
Eigen_PC	Benign	0.089
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L
PhyloP100		5.4
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.75	N
REVEL	Benign	0.087
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.029	D
Polyphen		0.0	B
Vest4		0.22
MVP		0.33
MPC		1.2
ClinPred		0.84	D
GERP RS		4.4
Varity_R		0.46
gMVP		0.79
Mutation Taster		=92/8	polymorphism

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

Other links and lift over

dbSNP: rs201021270; hg19: chr7-38765854;