chr14-67782782-C-T

Position:

chr14-67782782-C-T

Variant summary

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

The ENST00000347230.9(ZFYVE26):c.4370G>A(p.Cys1457Tyr) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.313 in 1,613,970 control chromosomes in the GnomAD database, including 85,746 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C1457S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.24 ( 5736 hom., cov: 32)

Exomes 𝑓: 0.32 ( 80010 hom. )

Consequence

ZFYVE26
ENST00000347230.9 missense, splice_region

Scores

Splicing: ADA: 0.00006575

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 2.73

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=0.0037769675).

BP6

Variant 14-67782782-C-T is Benign according to our data. Variant chr14-67782782-C-T is described in ClinVar as [Benign]. Clinvar id is 130782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-67782782-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.347 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZFYVE26	NM_015346.4 linkuse as main transcript	c.4370G>A	p.Cys1457Tyr	missense_variant, splice_region_variant	21/42	ENST00000347230.9	NP_056161.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZFYVE26	ENST00000347230.9 linkuse as main transcript	c.4370G>A	p.Cys1457Tyr	missense_variant, splice_region_variant	21/42	1	NM_015346.4	ENSP00000251119	P1

Frequencies

GnomAD3 genomes

AF:

0.244

AC:

37035

AN:

152080

Hom.:

5739

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0797

Gnomad AMI

AF:

0.349

Gnomad AMR

AF:

0.217

Gnomad ASJ

AF:

0.417

Gnomad EAS

AF:

0.0225

Gnomad SAS

AF:

0.225

Gnomad FIN

AF:

0.278

Gnomad MID

AF:

0.370

Gnomad NFE

AF:

0.351

Gnomad OTH

AF:

0.253

GnomAD3 exomes

AF:

0.262

AC:

65695

AN:

251120

Hom.:

10367

AF XY:

0.270

AC XY:

36635

AN XY:

135754

show subpopulations

Gnomad AFR exome

AF:

0.0719

Gnomad AMR exome

AF:

0.174

Gnomad ASJ exome

AF:

0.411

Gnomad EAS exome

AF:

0.0225

Gnomad SAS exome

AF:

0.217

Gnomad FIN exome

AF:

0.283

Gnomad NFE exome

AF:

0.347

Gnomad OTH exome

AF:

0.304

GnomAD4 exome

AF:

0.320

AC:

468192

AN:

1461772

Hom.:

80010

Cov.:

AF XY:

0.319

AC XY:

231801

AN XY:

727190

show subpopulations

Gnomad4 AFR exome

AF:

0.0669

Gnomad4 AMR exome

AF:

0.181

Gnomad4 ASJ exome

AF:

0.402

Gnomad4 EAS exome

AF:

0.0246

Gnomad4 SAS exome

AF:

0.218

Gnomad4 FIN exome

AF:

0.285

Gnomad4 NFE exome

AF:

0.353

Gnomad4 OTH exome

AF:

0.304

GnomAD4 genome

AF:

0.243

AC:

37024

AN:

152198

Hom.:

5736

Cov.:

AF XY:

0.238

AC XY:

17681

AN XY:

74402

show subpopulations

Gnomad4 AFR

AF:

0.0795

Gnomad4 AMR

AF:

0.217

Gnomad4 ASJ

AF:

0.417

Gnomad4 EAS

AF:

0.0226

Gnomad4 SAS

AF:

0.225

Gnomad4 FIN

AF:

0.278

Gnomad4 NFE

AF:

0.351

Gnomad4 OTH

AF:

0.249

Alfa

AF:

0.320

Hom.:

19470

Bravo

AF:

0.231

TwinsUK

AF:

0.355

AC:

1318

ALSPAC

AF:

0.362

AC:

1395

ESP6500AA

AF:

0.0874

AC:

385

ESP6500EA

AF:

0.354

AC:

3042

ExAC

AF:

0.263

AC:

31934

Asia WGS

AF:

0.134

AC:

467

AN:

3476

EpiCase

AF:

0.358

EpiControl

AF:

0.356

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 19, 2017	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	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. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 26, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 01, 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. -

Hereditary spastic paraplegia 15

Benign:3

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
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 benign is not then subjected to further curation. The score for this variant resulted in a classification of 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

Feb 01, 2024

- -

Hereditary spastic paraplegia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 12, 2016

- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.55

CADD

Benign

DANN

Benign

0.40

DEOGEN2

Benign

0.018

.;T

Eigen

Benign

-0.56

Eigen_PC

Benign

-0.47

FATHMM_MKL

Benign

0.29

LIST_S2

Benign

0.70

.;T

MetaRNN

Benign

0.0038

T;T

MetaSVM

Benign

-0.91

MutationTaster

Benign

1.0

P;P

PrimateAI

Benign

0.37

PROVEAN

Benign

0.93

N;N

REVEL

Benign

0.047

Sift

Benign

1.0

T;T

Sift4G

Benign

0.46

T;T

Polyphen

0.0

.;B

Vest4

0.15

MPC

0.28

ClinPred

0.0031

GERP RS

2.5

gMVP

0.13

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000066

dbscSNV1_RF

Benign

0.042

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