rs61746722

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_015346.4(ZFYVE26):c.5612G>A(p.Cys1871Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.012 in 1,613,904 control chromosomes in the GnomAD database, including 151 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C1871R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0096 ( 13 hom., cov: 32)

Exomes 𝑓: 0.012 ( 138 hom. )

Consequence

ZFYVE26
NM_015346.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 1.11

Publications

9 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), G2P, Orphanet, Myriad Women’s Health

ZFYVE26 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.002624333).

BP6

Variant 14-67769603-C-T is Benign according to our data. Variant chr14-67769603-C-T is described in ClinVar as Benign. ClinVar VariationId is 219560.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00957 (1457/152250) while in subpopulation NFE AF = 0.0151 (1028/68006). AF 95% confidence interval is 0.0143. There are 13 homozygotes in GnomAd4. There are 646 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 13 AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZFYVE26	NM_015346.4	MANE Select	c.5612G>A	p.Cys1871Tyr	missense	Exon 29 of 42	NP_056161.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ZFYVE26	ENST00000347230.9	TSL:1 MANE Select	c.5612G>A	p.Cys1871Tyr	missense	Exon 29 of 42	ENSP00000251119.5	Q68DK2-1
ZFYVE26	ENST00000555452.1	TSL:1	c.5612G>A	p.Cys1871Tyr	missense	Exon 29 of 35	ENSP00000450603.1	G3V2D8
ZFYVE26	ENST00000554523.5	TSL:1	n.5749G>A		non_coding_transcript_exon	Exon 29 of 41

Frequencies

GnomAD3 genomes

AF:

0.00958

AC:

1457

AN:

152132

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00270

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00799

Gnomad ASJ

AF:

0.0274

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00310

Gnomad FIN

AF:

0.00490

Gnomad MID

AF:

0.0350

Gnomad NFE

AF:

0.0151

Gnomad OTH

AF:

0.0100

GnomAD2 exomes

AF:

0.00999

AC:

2509

AN:

251074

AF XY:

0.0103

show subpopulations

Gnomad AFR exome

AF:

0.00301

Gnomad AMR exome

AF:

0.00645

Gnomad ASJ exome

AF:

0.0307

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00458

Gnomad NFE exome

AF:

0.0145

Gnomad OTH exome

AF:

0.0135

GnomAD4 exome

AF:

0.0122

AC:

17895

AN:

1461654

Hom.:

138

Cov.:

AF XY:

0.0123

AC XY:

8933

AN XY:

727136

show subpopulations

African (AFR)

AF:

0.00215

AC:

AN:

33470

American (AMR)

AF:

0.00742

AC:

332

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.0282

AC:

738

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00376

AC:

324

AN:

86250

European-Finnish (FIN)

AF:

0.00479

AC:

256

AN:

53410

Middle Eastern (MID)

AF:

0.0168

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.0136

AC:

15172

AN:

1111840

Other (OTH)

AF:

0.0150

AC:

904

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

1052

2105

3157

4210

5262

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

548

1096

1644

2192

2740

<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:

0.00957

AC:

1457

AN:

152250

Hom.:

Cov.:

AF XY:

0.00868

AC XY:

646

AN XY:

74454

show subpopulations

African (AFR)

AF:

0.00270

AC:

112

AN:

41552

American (AMR)

AF:

0.00798

AC:

122

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.0274

AC:

AN:

3464

East Asian (EAS)

AF:

0.000193

AC:

AN:

5178

South Asian (SAS)

AF:

0.00311

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00490

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.0377

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0151

AC:

1028

AN:

68006

Other (OTH)

AF:

0.00993

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

149

224

298

373

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.0136

Hom.:

Bravo

AF:

0.00967

TwinsUK

AF:

0.0116

AC:

ALSPAC

AF:

0.0130

AC:

ESP6500AA

AF:

0.00204

AC:

ESP6500EA

AF:

0.0124

AC:

107

ExAC

AF:

0.00961

AC:

1167

Asia WGS

AF:

0.00289

AC:

AN:

3478

EpiCase

AF:

0.0158

EpiControl

AF:

0.0166

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

Hereditary spastic paraplegia 15 (2)

not specified (2)

Hereditary spastic paraplegia (1)

Spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.52

CADD

Benign

(source)

DANN

Benign

0.29

DEOGEN2

Benign

0.0032

Eigen

Benign

-1.2

Eigen_PC

Benign

-0.92

FATHMM_MKL

Benign

0.62

LIST_S2

Benign

0.64

MetaRNN

Benign

0.0026

MetaSVM

Benign

-1.0

PhyloP100

1.1

PrimateAI

Benign

0.33

PROVEAN

Benign

1.6

REVEL

Benign

0.089

Sift

Benign

1.0

Sift4G

Benign

0.92

Polyphen

0.0

Vest4

0.25

MVP

0.12

MPC

0.28

ClinPred

0.0010

GERP RS

0.43

gMVP

0.49

Mutation Taster

=97/3

polymorphism

(source)

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

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

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

Computational scores

Splicing

Publications

Other links and lift over