rs3742885

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000347230.9(ZFYVE26):c.3308C>T(p.Pro1103Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0243 in 1,597,948 control chromosomes in the GnomAD database, including 1,179 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1103H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.048 ( 345 hom., cov: 32)

Exomes 𝑓: 0.022 ( 834 hom. )

Consequence

ZFYVE26
ENST00000347230.9 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 2.43

Variant links:

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]

ZFYVE26 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0013165772).

BP6

Variant 14-67785274-G-A is Benign according to our data. Variant chr14-67785274-G-A is described in ClinVar as [Benign]. Clinvar id is 130780.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-67785274-G-A is described in Lovd as [Benign]. Variant chr14-67785274-G-A is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.119 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZFYVE26	NM_015346.4 linkuse as main transcript	c.3308C>T	p.Pro1103Leu	missense_variant	19/42	ENST00000347230.9	NP_056161.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZFYVE26	ENST00000347230.9 linkuse as main transcript	c.3308C>T	p.Pro1103Leu	missense_variant	19/42	1	NM_015346.4	ENSP00000251119	P1

Frequencies

GnomAD3 genomes

AF:

0.0484

AC:

7357

AN:

152136

Hom.:

345

Cov.:

show subpopulations

Gnomad AFR

AF:

0.121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0195

Gnomad ASJ

AF:

0.0130

Gnomad EAS

AF:

0.127

Gnomad SAS

AF:

0.0224

Gnomad FIN

AF:

0.00904

Gnomad MID

AF:

0.0380

Gnomad NFE

AF:

0.0153

Gnomad OTH

AF:

0.0468

GnomAD3 exomes

AF:

0.0307

AC:

6698

AN:

218408

Hom.:

271

AF XY:

0.0285

AC XY:

3357

AN XY:

117862

show subpopulations

Gnomad AFR exome

AF:

0.129

Gnomad AMR exome

AF:

0.0122

Gnomad ASJ exome

AF:

0.0122

Gnomad EAS exome

AF:

0.127

Gnomad SAS exome

AF:

0.0196

Gnomad FIN exome

AF:

0.00827

Gnomad NFE exome

AF:

0.0166

Gnomad OTH exome

AF:

0.0228

GnomAD4 exome

AF:

0.0218

AC:

31453

AN:

1445694

Hom.:

834

Cov.:

AF XY:

0.0215

AC XY:

15454

AN XY:

717982

show subpopulations

Gnomad4 AFR exome

AF:

0.119

Gnomad4 AMR exome

AF:

0.0121

Gnomad4 ASJ exome

AF:

0.0131

Gnomad4 EAS exome

AF:

0.132

Gnomad4 SAS exome

AF:

0.0207

Gnomad4 FIN exome

AF:

0.00934

Gnomad4 NFE exome

AF:

0.0158

Gnomad4 OTH exome

AF:

0.0280

GnomAD4 genome

AF:

0.0484

AC:

7370

AN:

152254

Hom.:

345

Cov.:

AF XY:

0.0473

AC XY:

3518

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.121

Gnomad4 AMR

AF:

0.0195

Gnomad4 ASJ

AF:

0.0130

Gnomad4 EAS

AF:

0.127

Gnomad4 SAS

AF:

0.0226

Gnomad4 FIN

AF:

0.00904

Gnomad4 NFE

AF:

0.0153

Gnomad4 OTH

AF:

0.0468

Alfa

AF:

0.0225

Hom.:

211

Bravo

AF:

0.0539

TwinsUK

AF:

0.0178

AC:

ALSPAC

AF:

0.0145

AC:

ESP6500AA

AF:

0.120

AC:

529

ESP6500EA

AF:

0.0157

AC:

135

ExAC

AF:

0.0303

AC:

3636

Asia WGS

AF:

0.0690

AC:

241

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 02, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 25, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Hereditary spastic paraplegia 15

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -

Spastic paraplegia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Hereditary spastic paraplegia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 12, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.092

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.62

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0078

.;T

Eigen

Benign

-0.17

Eigen_PC

Benign

-0.095

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.70

.;T

MetaRNN

Benign

0.0013

T;T

MetaSVM

Benign

-1.1

MutationTaster

Benign

0.97

D;D

PrimateAI

Benign

0.36

PROVEAN

Benign

0.11

N;N

REVEL

Benign

0.065

Sift

Uncertain

0.018

D;D

Sift4G

Uncertain

0.0070

D;D

Polyphen

0.47

.;P

Vest4

0.084

MPC

0.17

ClinPred

0.013

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

gMVP

0.19

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over