14-67797704-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_015346.4(ZFYVE26):c.2300G>A(p.Arg767His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000954 in 1,614,176 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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. R767C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000064 ( 1 hom. )

Consequence

ZFYVE26
NM_015346.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 2.00

Publications

4 publications found

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 Gene-Disease associations (from GenCC):

hereditary spastic paraplegia 15
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Myriad Women’s Health, G2P

ZFYVE26 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.035185367).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZFYVE26	NM_015346.4 link	c.2300G>A	p.Arg767His	missense_variant	Exon 12 of 42	ENST00000347230.9	NP_056161.2	Q68DK2-1
ZFYVE26	XM_047431173.1 link	c.2300G>A	p.Arg767His	missense_variant	Exon 12 of 42		XP_047287129.1
ZFYVE26	XM_011536609.3 link	c.2300G>A	p.Arg767His	missense_variant	Exon 12 of 26		XP_011534911.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZFYVE26	ENST00000347230.9 link	c.2300G>A	p.Arg767His	missense_variant	Exon 12 of 42	1	NM_015346.4	ENSP00000251119.5		Q68DK2-1

Frequencies

GnomAD3 genomes

AF:

0.000361

AC:

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00113

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000119

AC:

AN:

251384

AF XY:

0.0000810

show subpopulations

Gnomad AFR exome

AF:

0.000923

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000791

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000643

AC:

AN:

1461856

Hom.:

Cov.:

AF XY:

0.0000550

AC XY:

AN XY:

727226

show subpopulations

African (AFR)

AF:

0.000836

AC:

AN:

33480

American (AMR)

AF:

0.0000447

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000580

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53394

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000477

AC:

AN:

1112010

Other (OTH)

AF:

0.0000828

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000394

AC:

AN:

152320

Hom.:

Cov.:

AF XY:

0.000403

AC XY:

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.00125

AC:

AN:

41568

American (AMR)

AF:

0.000131

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000882

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000249

Hom.:

Bravo

AF:

0.000298

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000173

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Spastic paraplegia

Uncertain:1

Sep 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 767 of the ZFYVE26 protein (p.Arg767His). This variant is present in population databases (rs146290086, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with ZFYVE26-related conditions. ClinVar contains an entry for this variant (Variation ID: 291143). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. 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. -

not specified

Uncertain:1

Mar 28, 2017

Athena Diagnostics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Uncertain:1

Apr 11, 2018

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.52

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.013

.;T

Eigen

Benign

-0.60

Eigen_PC

Benign

-0.48

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.69

.;T

M_CAP

Benign

0.0061

MetaRNN

Benign

0.035

T;T

MetaSVM

Benign

-1.0

PhyloP100

2.0

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.52

N;N

REVEL

Benign

0.029

Sift

Benign

0.12

T;T

Sift4G

Uncertain

0.037

D;D

Polyphen

0.0070

.;B

Vest4

0.33

MVP

0.085

MPC

0.20

ClinPred

0.046

GERP RS

3.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

gMVP

0.30

Mutation Taster

=95/5

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over