rs117228915

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_015346.4(ZFYVE26):c.1844C>T(p.Ser615Phe) variant causes a missense change. The variant allele was found at a frequency of 0.0109 in 1,613,474 control chromosomes in the GnomAD database, including 138 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0088 ( 11 hom., cov: 32)

Exomes 𝑓: 0.011 ( 127 hom. )

Consequence

ZFYVE26
NM_015346.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 5.20

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:

ZFYVE26 (HGNC:):

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=0.005330801).

BP6

Variant 14-67798418-G-A is Benign according to our data. Variant chr14-67798418-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 219559.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-67798418-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00884 (1346/152238) while in subpopulation NFE AF= 0.0139 (945/68028). AF 95% confidence interval is 0.0132. There are 11 homozygotes in gnomad4. There are 606 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZFYVE26	NM_015346.4 linkuse as main transcript	c.1844C>T	p.Ser615Phe	missense_variant	11/42	ENST00000347230.9	NP_056161.2	Q68DK2-1
ZFYVE26	XM_047431173.1 linkuse as main transcript	c.1844C>T	p.Ser615Phe	missense_variant	11/42		XP_047287129.1
ZFYVE26	XM_011536609.3 linkuse as main transcript	c.1844C>T	p.Ser615Phe	missense_variant	11/26		XP_011534911.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZFYVE26	ENST00000347230.9 linkuse as main transcript	c.1844C>T	p.Ser615Phe	missense_variant	11/42	1	NM_015346.4	ENSP00000251119.5		Q68DK2-1

Frequencies

GnomAD3 genomes

AF:

0.00886

AC:

1348

AN:

152122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00239

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00694

Gnomad ASJ

AF:

0.0268

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00436

Gnomad FIN

AF:

0.00538

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.0139

Gnomad OTH

AF:

0.00764

GnomAD3 exomes

AF:

0.00927

AC:

2328

AN:

251238

Hom.:

AF XY:

0.00944

AC XY:

1282

AN XY:

135776

show subpopulations

Gnomad AFR exome

AF:

0.00277

Gnomad AMR exome

AF:

0.00527

Gnomad ASJ exome

AF:

0.0286

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00356

Gnomad FIN exome

AF:

0.00481

Gnomad NFE exome

AF:

0.0134

Gnomad OTH exome

AF:

0.0131

GnomAD4 exome

AF:

0.0111

AC:

16249

AN:

1461236

Hom.:

127

Cov.:

AF XY:

0.0112

AC XY:

8147

AN XY:

726808

show subpopulations

Gnomad4 AFR exome

AF:

0.00212

Gnomad4 AMR exome

AF:

0.00642

Gnomad4 ASJ exome

AF:

0.0261

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00395

Gnomad4 FIN exome

AF:

0.00483

Gnomad4 NFE exome

AF:

0.0124

Gnomad4 OTH exome

AF:

0.0128

GnomAD4 genome

AF:

0.00884

AC:

1346

AN:

152238

Hom.:

Cov.:

AF XY:

0.00814

AC XY:

606

AN XY:

74432

show subpopulations

Gnomad4 AFR

AF:

0.00238

Gnomad4 AMR

AF:

0.00693

Gnomad4 ASJ

AF:

0.0268

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00436

Gnomad4 FIN

AF:

0.00538

Gnomad4 NFE

AF:

0.0139

Gnomad4 OTH

AF:

0.00756

Alfa

AF:

0.0132

Hom.:

Bravo

AF:

0.00863

TwinsUK

AF:

0.0113

AC:

ALSPAC

AF:

0.0119

AC:

ESP6500AA

AF:

0.00250

AC:

ESP6500EA

AF:

0.0122

AC:

105

ExAC

AF:

0.00892

AC:

1083

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.0154

EpiControl

AF:

0.0154

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2024	ZFYVE26: BP4, BS1, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 26, 2018	- -

Hereditary spastic paraplegia 15

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 06, 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. -

Spastic paraplegia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Hereditary spastic paraplegia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Oct 29, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.36

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.041

.;T

Eigen

Uncertain

0.66

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.83

.;T

MetaRNN

Benign

0.0053

T;T

MetaSVM

Benign

-0.84

PrimateAI

Benign

0.46

PROVEAN

Benign

-0.56

N;N

REVEL

Benign

0.14

Sift

Benign

0.086

T;D

Sift4G

Uncertain

0.017

D;D

Polyphen

0.98

.;D

Vest4

0.46

MVP

0.40

MPC

0.70

ClinPred

0.025

GERP RS

5.7

gMVP

0.41

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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