14-67767822-T-C

Variant names:

Variant summary

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

The NM_015346.4(ZFYVE26):c.5672A>G(p.Asn1891Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.972 in 1,614,112 control chromosomes in the GnomAD database, including 764,356 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.94 ( 67316 hom., cov: 32)

Exomes 𝑓: 0.98 ( 697040 hom. )

Consequence

ZFYVE26
NM_015346.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.377

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=7.4522825E-7).

BP6

Variant 14-67767822-T-C is Benign according to our data. Variant chr14-67767822-T-C is described in ClinVar as [Benign]. Clinvar id is 130783.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-67767822-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.98 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZFYVE26	NM_015346.4 link	c.5672A>G	p.Asn1891Ser	missense_variant	Exon 31 of 42	ENST00000347230.9	NP_056161.2	Q68DK2-1
ZFYVE26	XM_047431173.1 link	c.5672A>G	p.Asn1891Ser	missense_variant	Exon 31 of 42		XP_047287129.1
ZFYVE26	XM_047431174.1 link	c.3347A>G	p.Asn1116Ser	missense_variant	Exon 20 of 31		XP_047287130.1
ZFYVE26	XM_047431175.1 link	c.3254A>G	p.Asn1085Ser	missense_variant	Exon 20 of 31		XP_047287131.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZFYVE26	ENST00000347230.9 link	c.5672A>G	p.Asn1891Ser	missense_variant	Exon 31 of 42	1	NM_015346.4	ENSP00000251119.5		Q68DK2-1

Frequencies

GnomAD3 genomes

AF:

0.939

AC:

142761

AN:

152108

Hom.:

67275

Cov.:

show subpopulations

Gnomad AFR

AF:

0.851

Gnomad AMI

AF:

1.00

Gnomad AMR

AF:

0.922

Gnomad ASJ

AF:

0.996

Gnomad EAS

AF:

0.858

Gnomad SAS

AF:

0.971

Gnomad FIN

AF:

0.993

Gnomad MID

AF:

0.972

Gnomad NFE

AF:

0.987

Gnomad OTH

AF:

0.951

GnomAD3 exomes

AF:

0.954

AC:

239844

AN:

251352

Hom.:

114825

AF XY:

0.961

AC XY:

130500

AN XY:

135844

show subpopulations

Gnomad AFR exome

AF:

0.846

Gnomad AMR exome

AF:

0.894

Gnomad ASJ exome

AF:

0.996

Gnomad EAS exome

AF:

0.857

Gnomad SAS exome

AF:

0.974

Gnomad FIN exome

AF:

0.993

Gnomad NFE exome

AF:

0.986

Gnomad OTH exome

AF:

0.972

GnomAD4 exome

AF:

0.976

AC:

1426640

AN:

1461886

Hom.:

697040

Cov.:

AF XY:

0.977

AC XY:

710282

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.849

Gnomad4 AMR exome

AF:

0.896

Gnomad4 ASJ exome

AF:

0.995

Gnomad4 EAS exome

AF:

0.854

Gnomad4 SAS exome

AF:

0.973

Gnomad4 FIN exome

AF:

0.991

Gnomad4 NFE exome

AF:

0.987

Gnomad4 OTH exome

AF:

0.971

GnomAD4 genome

AF:

0.938

AC:

142863

AN:

152226

Hom.:

67316

Cov.:

AF XY:

0.938

AC XY:

69811

AN XY:

74422

show subpopulations

Gnomad4 AFR

AF:

0.851

Gnomad4 AMR

AF:

0.922

Gnomad4 ASJ

AF:

0.996

Gnomad4 EAS

AF:

0.858

Gnomad4 SAS

AF:

0.971

Gnomad4 FIN

AF:

0.993

Gnomad4 NFE

AF:

0.987

Gnomad4 OTH

AF:

0.950

Alfa

AF:

0.974

Hom.:

178753

Bravo

AF:

0.928

TwinsUK

AF:

0.984

AC:

3647

ALSPAC

AF:

0.988

AC:

3807

ESP6500AA

AF:

0.856

AC:

3770

ESP6500EA

AF:

0.986

AC:

8478

ExAC

AF:

0.955

AC:

115895

Asia WGS

AF:

0.916

AC:

3185

AN:

3478

EpiCase

AF:

0.988

EpiControl

AF:

0.987

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 24, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 21, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

Hereditary spastic paraplegia 15

Benign:2

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Spastic paraplegia

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary spastic paraplegia

Benign:1

Dec 12, 2016

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.84

BayesDel_noAF

Benign

-0.84

CADD

Benign

0.083

DANN

Benign

0.11

DEOGEN2

Benign

0.0024

.;T

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.024

LIST_S2

Benign

0.12

.;T

MetaRNN

Benign

7.5e-7

T;T

MetaSVM

Benign

-1.0

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.12

N;N

REVEL

Benign

0.015

Sift

Benign

1.0

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0

.;B

Vest4

0.012

MPC

0.13

ClinPred

0.00015

GERP RS

-2.7

gMVP

0.078

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

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