Variant summary

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

The NM_015346.4(ZFYVE26):c.5401G>A(p.Ala1801Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000722 in 1,613,106 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 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. A1801G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00055 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00074 ( 0 hom. )

Consequence

ZFYVE26
NM_015346.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6B:2O:1

Conservation

PhyloP100: 4.95

Publications

2 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=0.02182737).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015346.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZFYVE26	NM_015346.4	MANE Select	c.5401G>A	p.Ala1801Thr	missense	Exon 28 of 42	NP_056161.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ZFYVE26	ENST00000347230.9	TSL:1 MANE Select	c.5401G>A	p.Ala1801Thr	missense	Exon 28 of 42	ENSP00000251119.5
ZFYVE26	ENST00000555452.1	TSL:1	c.5401G>A	p.Ala1801Thr	missense	Exon 28 of 35	ENSP00000450603.1
ZFYVE26	ENST00000554523.5	TSL:1	n.5538G>A		non_coding_transcript_exon	Exon 28 of 41

Frequencies

GnomAD3 genomes

AF:

0.000546

AC:

AN:

152048

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000787

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:

0.000956

Gnomad OTH

AF:

0.000955

GnomAD2 exomes

AF:

0.000377

AC:

AN:

249342

AF XY:

0.000379

show subpopulations

Gnomad AFR exome

AF:

0.000186

Gnomad AMR exome

AF:

0.000175

Gnomad ASJ exome

AF:

0.000299

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000710

Gnomad OTH exome

AF:

0.000329

GnomAD4 exome

AF:

0.000740

AC:

1081

AN:

1460940

Hom.:

Cov.:

AF XY:

0.000694

AC XY:

504

AN XY:

726674

show subpopulations

African (AFR)

AF:

0.000149

AC:

AN:

33458

American (AMR)

AF:

0.000179

AC:

AN:

44606

Ashkenazi Jewish (ASJ)

AF:

0.000383

AC:

AN:

26114

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86024

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53394

Middle Eastern (MID)

AF:

0.000181

AC:

AN:

5516

European-Non Finnish (NFE)

AF:

0.000915

AC:

1017

AN:

1111784

Other (OTH)

AF:

0.000663

AC:

AN:

60348

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

124

187

249

311

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

102

136

170

<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:

0.000545

AC:

AN:

152166

Hom.:

Cov.:

AF XY:

0.000511

AC XY:

AN XY:

74380

show subpopulations

African (AFR)

AF:

0.0000963

AC:

AN:

41520

American (AMR)

AF:

0.000786

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5162

South Asian (SAS)

AF:

0.00

AC:

AN:

4810

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10598

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000956

AC:

AN:

68008

Other (OTH)

AF:

0.000945

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

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:

0.000777

Hom.:

Bravo

AF:

0.000544

TwinsUK

AF:

0.00189

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.000305

AC:

EpiCase

AF:

0.000763

EpiControl

AF:

0.000953

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Hereditary spastic paraplegia 15 (3)

not specified (1)

Spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.50

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.015

Eigen

Benign

-0.12

Eigen_PC

Benign

-0.017

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.90

M_CAP

Benign

0.012

MetaRNN

Benign

0.022

MetaSVM

Benign

-1.1

PhyloP100

5.0

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.48

REVEL

Benign

0.027

Sift

Benign

0.18

Sift4G

Uncertain

0.050

Polyphen

0.29

Vest4

0.28

MVP

0.15

MPC

0.35

ClinPred

0.089

GERP RS

3.9

gMVP

0.14

Mutation Taster

=93/7

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

rs138965635

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over