rs140756827

Positions:

chr14-67783430-C-T

Variant summary

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

The NM_015346.4(ZFYVE26):c.3722G>A(p.Arg1241Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00325 in 1,614,066 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0026 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0033 ( 17 hom. )

Consequence

ZFYVE26
NM_015346.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:10

Conservation

PhyloP100: -0.433

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004694402).

BP6

Variant 14-67783430-C-T is Benign according to our data. Variant chr14-67783430-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 288592.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=1, Benign=3}. Variant chr14-67783430-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00265 (403/152218) while in subpopulation AMR AF= 0.00445 (68/15298). AF 95% confidence interval is 0.0036. There are 1 homozygotes in gnomad4. There are 193 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 17 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZFYVE26	NM_015346.4 linkuse as main transcript	c.3722G>A	p.Arg1241Gln	missense_variant	21/42	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.3722G>A	p.Arg1241Gln	missense_variant	21/42	1	NM_015346.4	ENSP00000251119.5		Q68DK2-1

Frequencies

GnomAD3 genomes

AF:

0.00265

AC:

403

AN:

152102

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000411

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00445

Gnomad ASJ

AF:

0.00894

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00332

Gnomad FIN

AF:

0.00113

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00354

Gnomad OTH

AF:

0.00669

GnomAD3 exomes

AF:

0.00309

AC:

776

AN:

251098

Hom.:

AF XY:

0.00335

AC XY:

454

AN XY:

135692

show subpopulations

Gnomad AFR exome

AF:

0.000492

Gnomad AMR exome

AF:

0.00315

Gnomad ASJ exome

AF:

0.00914

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00265

Gnomad FIN exome

AF:

0.00176

Gnomad NFE exome

AF:

0.00360

Gnomad OTH exome

AF:

0.00637

GnomAD4 exome

AF:

0.00331

AC:

4844

AN:

1461848

Hom.:

Cov.:

AF XY:

0.00346

AC XY:

2518

AN XY:

727220

show subpopulations

Gnomad4 AFR exome

AF:

0.000568

Gnomad4 AMR exome

AF:

0.00309

Gnomad4 ASJ exome

AF:

0.0103

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00344

Gnomad4 FIN exome

AF:

0.00144

Gnomad4 NFE exome

AF:

0.00323

Gnomad4 OTH exome

AF:

0.00495

GnomAD4 genome

AF:

0.00265

AC:

403

AN:

152218

Hom.:

Cov.:

AF XY:

0.00259

AC XY:

193

AN XY:

74436

show subpopulations

Gnomad4 AFR

AF:

0.000409

Gnomad4 AMR

AF:

0.00445

Gnomad4 ASJ

AF:

0.00894

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00332

Gnomad4 FIN

AF:

0.00113

Gnomad4 NFE

AF:

0.00354

Gnomad4 OTH

AF:

0.00662

Alfa

AF:

0.00408

Hom.:

Bravo

AF:

0.00298

TwinsUK

AF:

0.00189

AC:

ALSPAC

AF:

0.00311

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00372

AC:

ExAC

AF:

0.00283

AC:

344

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.00534

EpiControl

AF:

0.00616

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:10

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:6

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely 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	GeneDx	Mar 14, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	ZFYVE26: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 18, 2017	- -

Hereditary spastic paraplegia 15

Uncertain:1Benign:1

Benign, criteria provided, single submitter	clinical testing	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	Jul 23, 2020	- -
Uncertain significance, 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, 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. -

Spastic paraplegia

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jun 17, 2016

- -

Hereditary spastic paraplegia

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Oct 01, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.67

CADD

Benign

2.4

DANN

Uncertain

0.98

DEOGEN2

Benign

0.012

.;T

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.038

LIST_S2

Benign

0.66

.;T

M_CAP

Benign

0.0040

MetaRNN

Benign

0.0047

T;T

MetaSVM

Benign

-1.0

PrimateAI

Benign

0.20

PROVEAN

Benign

-0.90

N;N

REVEL

Benign

0.11

Sift

Benign

0.13

T;T

Sift4G

Benign

0.096

T;T

Polyphen

0.99

.;D

Vest4

0.054

MVP

0.040

MPC

0.19

ClinPred

0.018

GERP RS

-11

gMVP

0.10

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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