rs367857763

chr14-67762285-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015346.4(ZFYVE26):c.6287T>C(p.Leu2096Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000479 in 1,461,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: ZFYVE26 NM_015346.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.89

Genes affected

ZFYVE26 (HGNC:20761): (zinc finger FYVE-type containing 26) This gene encodes a protein which contains a FYVE zinc finger binding domain. The presence of this domain is thought to target these proteins to membrane lipids through interaction with phospholipids in the membrane. Mutations in this gene are associated with autosomal recessive spastic paraplegia-15. [provided by RefSeq, Oct 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14556888).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZFYVE26	NM_015346.4	c.6287T>C	p.Leu2096Pro	missense_variant	34/42	ENST00000347230.9
ZFYVE26	XM_047431173.1	c.6287T>C	p.Leu2096Pro	missense_variant	34/42
ZFYVE26	XM_047431174.1	c.3962T>C	p.Leu1321Pro	missense_variant	23/31
ZFYVE26	XM_047431175.1	c.3869T>C	p.Leu1290Pro	missense_variant	23/31

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZFYVE26	ENST00000347230.9	c.6287T>C	p.Leu2096Pro	missense_variant	34/42	1	NM_015346.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000279 AC: 7 AN: 251332 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135836

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461894 Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 32

Alfa AF: 0.000223 Hom.: 0

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Spastic paraplegia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 13, 2021

This sequence change replaces leucine with proline at codon 2096 of the ZFYVE26 protein (p.Leu2096Pro). The leucine residue is moderately conserved and there is a moderate physicochemical difference between leucine and proline. This variant has not been reported in the literature in individuals affected with ZFYVE26-related conditions. ClinVar contains an entry for this variant (Variation ID: 216692). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The proline amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.039	T
BayesDel_noAF	Benign	-0.10
Cadd	Benign	23
Dann	Uncertain	0.98
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.031
FATHMM_MKL	Uncertain	0.93	D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.15	T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.4	N;N
REVEL	Benign	0.16
Sift	Benign	0.12	T;T
Sift4G	Benign	0.15	T;T
Polyphen		0.12	.;B
Vest4		0.39
MVP		0.29
MPC		0.29
ClinPred		0.098	T
GERP RS		4.3
gMVP		0.48

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

LitVar

Other links and lift over

dbSNP: rs367857763; hg19: chr14-68229002; COSMIC: COSV100720719; COSMIC: COSV100720719;