rs1060505031

Variant names:

• chr22-17600079-A-G
• rs1060505031
• NM_001696.4:c.383T>C

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_001696.4(ATP6V1E1):​c.383T>C​(p.Leu128Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L128V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: ATP6V1E1 NM_001696.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.93
• Publications: 1 publications found

Genes affected

ATP6V1E1 (HGNC:857): (ATPase H+ transporting V1 subunit E1) This gene encodes a component of vacuolar ATPase (V-ATPase), a multisubunit enzyme that mediates acidification of eukaryotic intracellular organelles. V-ATPase dependent organelle acidification is necessary for such intracellular processes as protein sorting, zymogen activation, receptor-mediated endocytosis, and synaptic vesicle proton gradient generation. V-ATPase is composed of a cytosolic V1 domain and a transmembrane V0 domain. The V1 domain consists of three A, three B, and two G subunits, as well as a C, D, E, F, and H subunit. The V1 domain contains the ATP catalytic site. This gene encodes alternate transcriptional splice variants, encoding different V1 domain E subunit isoforms. Pseudogenes for this gene have been found in the genome. [provided by RefSeq, Jul 2008]

ATP6V1E1 Gene-Disease associations (from GenCC):

• autosomal recessive cutis laxa type 2C

  Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P
• autosomal recessive cutis laxa type 2, classic type

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.864
• PP5: Variant 22-17600079-A-G is Pathogenic according to our data. Variant chr22-17600079-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 417759.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP6V1E1	NM_001696.4	c.383T>C	p.Leu128Pro	missense_variant	Exon 6 of 9	ENST00000253413.10	NP_001687.1
ATP6V1E1	NM_001039366.1	c.317T>C	p.Leu106Pro	missense_variant	Exon 5 of 8		NP_001034455.1
ATP6V1E1	NM_001039367.1	c.293T>C	p.Leu98Pro	missense_variant	Exon 5 of 8		NP_001034456.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP6V1E1	ENST00000253413.10	c.383T>C	p.Leu128Pro	missense_variant	Exon 6 of 9	1	NM_001696.4	ENSP00000253413.5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Autosomal recessive cutis laxa type 2C Pathogenic:1

Mar 22, 2019

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	T;.;.;T
Eigen	Pathogenic	0.74
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;D;D;D
M_CAP	Benign	0.041	D
MetaRNN	Pathogenic	0.86	D;D;D;D
MetaSVM	Uncertain	0.24	D
MutationAssessor	Pathogenic	3.8	H;.;.;.
PhyloP100		7.9
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-6.0	D;D;D;D
REVEL	Uncertain	0.59
Sift	Uncertain	0.022	D;D;D;D
Sift4G	Benign	0.16	T;D;T;.
Polyphen		0.97	D;.;.;.
Vest4		0.98
MutPred		0.47		Gain of sheet (P = 0.1208);.;.;.;
MVP		0.55
MPC		1.1
ClinPred		0.99	D
GERP RS		4.7
Varity_R		0.94
gMVP		0.85
Mutation Taster		=15/85	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1060505031; hg19: chr22-18082845;