rs374605354

Positions:

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_015346.4(ZFYVE26):c.3025C>T(p.Arg1009Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000141 in 1,293,332 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1009G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000065 ( 0 hom., cov: 30)

Exomes 𝑓: 0.00015 ( 4 hom. )

Consequence

ZFYVE26
NM_015346.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.23

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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.026570886).

BS1

Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.00015 (175/1170360) while in subpopulation SAS AF= 0.00176 (135/76712). AF 95% confidence interval is 0.00152. There are 4 homozygotes in gnomad4_exome. There are 130 alleles in male gnomad4_exome subpopulation. Median coverage is 40. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZFYVE26	NM_015346.4 linkuse as main transcript	c.3025C>T	p.Arg1009Trp	missense_variant	17/42	ENST00000347230.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZFYVE26	ENST00000347230.9 linkuse as main transcript	c.3025C>T	p.Arg1009Trp	missense_variant	17/42	1	NM_015346.4	P1

Frequencies

GnomAD3 genomes

AF:

0.0000651

AC:

AN:

122892

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000296

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00134

Gnomad FIN

AF:

0.000225

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000160

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000269

AC:

AN:

234122

Hom.:

AF XY:

0.000370

AC XY:

AN XY:

126972

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00201

Gnomad FIN exome

AF:

0.0000951

Gnomad NFE exome

AF:

0.0000279

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000150

AC:

175

AN:

1170360

Hom.:

Cov.:

AF XY:

0.000222

AC XY:

130

AN XY:

585412

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00176

Gnomad4 FIN exome

AF:

0.000155

Gnomad4 NFE exome

AF:

0.0000281

Gnomad4 OTH exome

AF:

0.000150

GnomAD4 genome

AF:

0.0000651

AC:

AN:

122972

Hom.:

Cov.:

AF XY:

0.0000707

AC XY:

AN XY:

56610

show subpopulations

Gnomad4 AFR

AF:

0.0000295

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00134

Gnomad4 FIN

AF:

0.000225

Gnomad4 NFE

AF:

0.0000160

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000329

Hom.:

Bravo

AF:

0.0000453

ExAC

AF:

0.000264

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Spastic paraplegia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 27, 2021

This sequence change replaces arginine with tryptophan at codon 1009 of the ZFYVE26 protein (p.Arg1009Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs374605354, ExAC 0.2%). This variant has not been reported in the literature in individuals affected with ZFYVE26-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.36

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.068

.;T

Eigen

Benign

-0.012

Eigen_PC

Benign

-0.084

FATHMM_MKL

Benign

0.74

LIST_S2

Benign

0.84

.;T

M_CAP

Benign

0.079

MetaRNN

Benign

0.027

T;T

MetaSVM

Benign

-0.74

MutationTaster

Benign

0.86

D;D

PrimateAI

Benign

0.33

PROVEAN

Benign

-2.2

N;N

REVEL

Benign

0.20

Sift

Uncertain

0.0030

D;D

Sift4G

Pathogenic

0.0010

D;D

Polyphen

1.0

.;D

Vest4

0.53

MutPred

0.44

Loss of disorder (P = 0.0089);Loss of disorder (P = 0.0089);

MVP

0.48

MPC

0.63

ClinPred

0.23

GERP RS

2.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

gMVP

0.29

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