14-67767816-C-A

Position:

chr14-67767816-C-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_015346.4(ZFYVE26):c.5678G>T(p.Ser1893Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00821 in 1,614,132 control chromosomes in the GnomAD database, including 71 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1893G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0070 ( 5 hom., cov: 31)

Exomes 𝑓: 0.0083 ( 66 hom. )

Consequence

ZFYVE26
NM_015346.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 0.740

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005324453).

BP6

Variant 14-67767816-C-A is Benign according to our data. Variant chr14-67767816-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 188139.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=5}. Variant chr14-67767816-C-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00701 (1068/152256) while in subpopulation NFE AF= 0.00913 (621/68030). AF 95% confidence interval is 0.00853. There are 5 homozygotes in gnomad4. There are 527 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
ZFYVE26	NM_015346.4 linkuse as main transcript	c.5678G>T	p.Ser1893Ile	missense_variant	31/42	ENST00000347230.9
ZFYVE26	XM_047431173.1 linkuse as main transcript	c.5678G>T	p.Ser1893Ile	missense_variant	31/42
ZFYVE26	XM_047431174.1 linkuse as main transcript	c.3353G>T	p.Ser1118Ile	missense_variant	20/31
ZFYVE26	XM_047431175.1 linkuse as main transcript	c.3260G>T	p.Ser1087Ile	missense_variant	20/31

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZFYVE26	ENST00000347230.9 linkuse as main transcript	c.5678G>T	p.Ser1893Ile	missense_variant	31/42	1	NM_015346.4	P1

Frequencies

GnomAD3 genomes

AF:

0.00702

AC:

1068

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00152

Gnomad AMI

AF:

0.00439

Gnomad AMR

AF:

0.00543

Gnomad ASJ

AF:

0.0184

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00186

Gnomad FIN

AF:

0.0192

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00914

Gnomad OTH

AF:

0.00860

GnomAD3 exomes

AF:

0.00863

AC:

2170

AN:

251332

Hom.:

AF XY:

0.00869

AC XY:

1180

AN XY:

135828

show subpopulations

Gnomad AFR exome

AF:

0.00148

Gnomad AMR exome

AF:

0.00546

Gnomad ASJ exome

AF:

0.0181

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00412

Gnomad FIN exome

AF:

0.0195

Gnomad NFE exome

AF:

0.0102

Gnomad OTH exome

AF:

0.0111

GnomAD4 exome

AF:

0.00833

AC:

12177

AN:

1461876

Hom.:

Cov.:

AF XY:

0.00841

AC XY:

6116

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.00137

Gnomad4 AMR exome

AF:

0.00577

Gnomad4 ASJ exome

AF:

0.0194

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00385

Gnomad4 FIN exome

AF:

0.0191

Gnomad4 NFE exome

AF:

0.00849

Gnomad4 OTH exome

AF:

0.00863

GnomAD4 genome

AF:

0.00701

AC:

1068

AN:

152256

Hom.:

Cov.:

AF XY:

0.00708

AC XY:

527

AN XY:

74440

show subpopulations

Gnomad4 AFR

AF:

0.00154

Gnomad4 AMR

AF:

0.00543

Gnomad4 ASJ

AF:

0.0184

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00187

Gnomad4 FIN

AF:

0.0192

Gnomad4 NFE

AF:

0.00913

Gnomad4 OTH

AF:

0.00851

Alfa

AF:

0.00817

Hom.:

Bravo

AF:

0.00621

TwinsUK

AF:

0.00647

AC:

ALSPAC

AF:

0.00882

AC:

ESP6500AA

AF:

0.00182

AC:

ESP6500EA

AF:

0.0105

AC:

ExAC

AF:

0.00806

AC:

979

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.00981

EpiControl

AF:

0.0104

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	ZFYVE26: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 28, 2018	- -

Hereditary spastic paraplegia 15

Uncertain:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 08, 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

Invitae

Jan 31, 2024

- -

Hereditary spastic paraplegia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jan 21, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.56

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.026

.;T

Eigen

Benign

-0.22

Eigen_PC

Benign

-0.34

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.72

.;T

MetaRNN

Benign

0.0053

T;T

MetaSVM

Benign

-1.0

MutationTaster

Benign

0.89

N;N

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.72

N;N

REVEL

Benign

0.075

Sift

Benign

0.23

T;T

Sift4G

Uncertain

0.046

D;D

Polyphen

0.99

.;D

Vest4

0.29

MVP

0.25

MPC

0.28

ClinPred

0.013

GERP RS

1.6

gMVP

0.37

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

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