rs61746722

Positions:

chr14-67769603-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.5612G>A(p.Cys1871Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.012 in 1,613,904 control chromosomes in the GnomAD database, including 151 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0096 ( 13 hom., cov: 32)

Exomes 𝑓: 0.012 ( 138 hom. )

Consequence

ZFYVE26
NM_015346.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.11

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=0.002624333).

BP6

Variant 14-67769603-C-T is Benign according to our data. Variant chr14-67769603-C-T is described in ClinVar as [Benign]. Clinvar id is 219560.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-67769603-C-T is described in Lovd as [Likely_benign]. Variant chr14-67769603-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00957 (1457/152250) while in subpopulation NFE AF= 0.0151 (1028/68006). AF 95% confidence interval is 0.0143. There are 13 homozygotes in gnomad4. There are 646 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZFYVE26	NM_015346.4 linkuse as main transcript	c.5612G>A	p.Cys1871Tyr	missense_variant	29/42	ENST00000347230.9	NP_056161.2	Q68DK2-1
ZFYVE26	XM_047431173.1 linkuse as main transcript	c.5612G>A	p.Cys1871Tyr	missense_variant	29/42		XP_047287129.1
ZFYVE26	XM_047431174.1 linkuse as main transcript	c.3287G>A	p.Cys1096Tyr	missense_variant	18/31		XP_047287130.1
ZFYVE26	XM_047431175.1 linkuse as main transcript	c.3194G>A	p.Cys1065Tyr	missense_variant	18/31		XP_047287131.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZFYVE26	ENST00000347230.9 linkuse as main transcript	c.5612G>A	p.Cys1871Tyr	missense_variant	29/42	1	NM_015346.4	ENSP00000251119.5		Q68DK2-1

Frequencies

GnomAD3 genomes

AF:

0.00958

AC:

1457

AN:

152132

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00270

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00799

Gnomad ASJ

AF:

0.0274

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00310

Gnomad FIN

AF:

0.00490

Gnomad MID

AF:

0.0350

Gnomad NFE

AF:

0.0151

Gnomad OTH

AF:

0.0100

GnomAD3 exomes

AF:

0.00999

AC:

2509

AN:

251074

Hom.:

AF XY:

0.0103

AC XY:

1402

AN XY:

135686

show subpopulations

Gnomad AFR exome

AF:

0.00301

Gnomad AMR exome

AF:

0.00645

Gnomad ASJ exome

AF:

0.0307

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00340

Gnomad FIN exome

AF:

0.00458

Gnomad NFE exome

AF:

0.0145

Gnomad OTH exome

AF:

0.0135

GnomAD4 exome

AF:

0.0122

AC:

17895

AN:

1461654

Hom.:

138

Cov.:

AF XY:

0.0123

AC XY:

8933

AN XY:

727136

show subpopulations

Gnomad4 AFR exome

AF:

0.00215

Gnomad4 AMR exome

AF:

0.00742

Gnomad4 ASJ exome

AF:

0.0282

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00376

Gnomad4 FIN exome

AF:

0.00479

Gnomad4 NFE exome

AF:

0.0136

Gnomad4 OTH exome

AF:

0.0150

GnomAD4 genome

AF:

0.00957

AC:

1457

AN:

152250

Hom.:

Cov.:

AF XY:

0.00868

AC XY:

646

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.00270

Gnomad4 AMR

AF:

0.00798

Gnomad4 ASJ

AF:

0.0274

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00311

Gnomad4 FIN

AF:

0.00490

Gnomad4 NFE

AF:

0.0151

Gnomad4 OTH

AF:

0.00993

Alfa

AF:

0.0145

Hom.:

Bravo

AF:

0.00967

TwinsUK

AF:

0.0116

AC:

ALSPAC

AF:

0.0130

AC:

ESP6500AA

AF:

0.00204

AC:

ESP6500EA

AF:

0.0124

AC:

107

ExAC

AF:

0.00961

AC:

1167

Asia WGS

AF:

0.00289

AC:

AN:

3478

EpiCase

AF:

0.0158

EpiControl

AF:

0.0166

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2024	ZFYVE26: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 24, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Hereditary spastic paraplegia 15

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -

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

Nov 17, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.52

CADD

Benign

DANN

Benign

0.29

DEOGEN2

Benign

0.0032

.;T

Eigen

Benign

-1.2

Eigen_PC

Benign

-0.92

FATHMM_MKL

Benign

0.62

LIST_S2

Benign

0.64

.;T

MetaRNN

Benign

0.0026

T;T

MetaSVM

Benign

-1.0

PrimateAI

Benign

0.33

PROVEAN

Benign

1.6

N;N

REVEL

Benign

0.089

Sift

Benign

1.0

T;T

Sift4G

Benign

0.92

T;T

Polyphen

0.0

.;B

Vest4

0.25

MVP

0.12

MPC

0.28

ClinPred

0.0010

GERP RS

0.43

gMVP

0.49

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