14-67789528-C-T

Position:

chr14-67789528-C-T

Variant summary

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

The NM_015346.4(ZFYVE26):c.2826G>A(p.Met942Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0112 in 1,614,134 control chromosomes in the GnomAD database, including 154 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.0081 ( 15 hom., cov: 33)

Exomes 𝑓: 0.012 ( 139 hom. )

Consequence

ZFYVE26
NM_015346.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -2.78

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=0.0047784746).

BP6

Variant 14-67789528-C-T is Benign according to our data. Variant chr14-67789528-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 220334.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-67789528-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0081 (1234/152298) while in subpopulation NFE AF= 0.0128 (869/68024). AF 95% confidence interval is 0.0121. There are 15 homozygotes in gnomad4. There are 557 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 15 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZFYVE26	NM_015346.4 linkuse as main transcript	c.2826G>A	p.Met942Ile	missense_variant	16/42	ENST00000347230.9	NP_056161.2	Q68DK2-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZFYVE26	ENST00000347230.9 linkuse as main transcript	c.2826G>A	p.Met942Ile	missense_variant	16/42	1	NM_015346.4	ENSP00000251119.5		Q68DK2-1

Frequencies

GnomAD3 genomes

AF:

0.00812

AC:

1235

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00217

Gnomad AMI

AF:

0.0493

Gnomad AMR

AF:

0.00465

Gnomad ASJ

AF:

0.0306

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00331

Gnomad FIN

AF:

0.00198

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0128

Gnomad OTH

AF:

0.00670

GnomAD3 exomes

AF:

0.00834

AC:

2091

AN:

250810

Hom.:

AF XY:

0.00834

AC XY:

1132

AN XY:

135652

show subpopulations

Gnomad AFR exome

AF:

0.00235

Gnomad AMR exome

AF:

0.00408

Gnomad ASJ exome

AF:

0.0283

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00320

Gnomad FIN exome

AF:

0.00176

Gnomad NFE exome

AF:

0.0126

Gnomad OTH exome

AF:

0.00980

GnomAD4 exome

AF:

0.0115

AC:

16838

AN:

1461836

Hom.:

139

Cov.:

AF XY:

0.0112

AC XY:

8155

AN XY:

727216

show subpopulations

Gnomad4 AFR exome

AF:

0.00221

Gnomad4 AMR exome

AF:

0.00407

Gnomad4 ASJ exome

AF:

0.0300

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00322

Gnomad4 FIN exome

AF:

0.00204

Gnomad4 NFE exome

AF:

0.0132

Gnomad4 OTH exome

AF:

0.0105

GnomAD4 genome

AF:

0.00810

AC:

1234

AN:

152298

Hom.:

Cov.:

AF XY:

0.00748

AC XY:

557

AN XY:

74482

show subpopulations

Gnomad4 AFR

AF:

0.00217

Gnomad4 AMR

AF:

0.00464

Gnomad4 ASJ

AF:

0.0306

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.00311

Gnomad4 FIN

AF:

0.00198

Gnomad4 NFE

AF:

0.0128

Gnomad4 OTH

AF:

0.00663

Alfa

AF:

0.0125

Hom.:

Bravo

AF:

0.00786

TwinsUK

AF:

0.0135

AC:

ALSPAC

AF:

0.0130

AC:

ESP6500AA

AF:

0.00295

AC:

ESP6500EA

AF:

0.0145

AC:

125

ExAC

AF:

0.00806

AC:

979

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.0132

EpiControl

AF:

0.0122

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 27, 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. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 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	Jan 16, 2018	- -

Hereditary spastic paraplegia 15

Benign:2

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely 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

Jan 31, 2024

- -

Hereditary spastic paraplegia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Aug 17, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.71

BayesDel_noAF

Benign

-0.78

CADD

Benign

0.0010

DANN

Benign

0.81

DEOGEN2

Benign

0.0028

.;T

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.030

LIST_S2

Benign

0.28

.;T

MetaRNN

Benign

0.0048

T;T

MetaSVM

Benign

-1.0

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.080

N;N

REVEL

Benign

0.044

Sift

Benign

0.25

T;T

Sift4G

Benign

0.39

T;T

Polyphen

0.0

.;B

Vest4

0.19

MutPred

0.24

Loss of disorder (P = 0.1701);Loss of disorder (P = 0.1701);

MVP

0.099

MPC

0.18

ClinPred

0.0067

GERP RS

-11

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

gMVP

0.35

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