rs151166497

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_015346.4(ZFYVE26):c.7055C>T(p.Thr2352Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00312 in 1,614,242 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T2352T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0030 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0031 ( 19 hom. )

Consequence

ZFYVE26
NM_015346.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:6

Conservation

PhyloP100: 5.62

Publications

10 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.006386131).

BP6

Variant 14-67754144-G-A is Benign according to our data. Variant chr14-67754144-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 188338.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00305 (464/152348) while in subpopulation NFE AF = 0.00373 (254/68026). AF 95% confidence interval is 0.00336. There are 2 homozygotes in GnomAd4. There are 261 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 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.7055C>T	p.Thr2352Ile	missense	Exon 38 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.7055C>T	p.Thr2352Ile	missense	Exon 38 of 42	ENSP00000251119.5	Q68DK2-1
ZFYVE26	ENST00000557306.1	TSL:1	c.593C>T	p.Thr198Ile	missense	Exon 4 of 7	ENSP00000452142.1	A0A2H2FF08
ZFYVE26	ENST00000554523.5	TSL:1	n.7810C>T		non_coding_transcript_exon	Exon 37 of 41

Frequencies

GnomAD3 genomes

AF:

0.00305

AC:

464

AN:

152230

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000651

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00229

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000829

Gnomad FIN

AF:

0.0124

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00373

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00293

AC:

738

AN:

251472

AF XY:

0.00304

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.00159

Gnomad ASJ exome

AF:

0.00218

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0103

Gnomad NFE exome

AF:

0.00327

Gnomad OTH exome

AF:

0.00407

GnomAD4 exome

AF:

0.00313

AC:

4576

AN:

1461894

Hom.:

Cov.:

AF XY:

0.00308

AC XY:

2240

AN XY:

727248

show subpopulations

African (AFR)

AF:

0.000478

AC:

AN:

33480

American (AMR)

AF:

0.00192

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00306

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00107

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00932

AC:

498

AN:

53420

Middle Eastern (MID)

AF:

0.00243

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00326

AC:

3630

AN:

1112012

Other (OTH)

AF:

0.00265

AC:

160

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

303

607

910

1214

1517

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

138

276

414

552

690

<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:

0.00305

AC:

464

AN:

152348

Hom.:

Cov.:

AF XY:

0.00350

AC XY:

261

AN XY:

74500

show subpopulations

African (AFR)

AF:

0.000649

AC:

AN:

41586

American (AMR)

AF:

0.00229

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00173

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.000829

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0124

AC:

132

AN:

10620

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00373

AC:

254

AN:

68026

Other (OTH)

AF:

0.00237

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

113

141

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:

0.00311

Hom.:

Bravo

AF:

0.00273

TwinsUK

AF:

0.00243

AC:

ALSPAC

AF:

0.00337

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00360

AC:

ExAC

AF:

0.00255

AC:

310

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00344

EpiControl

AF:

0.00332

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hereditary spastic paraplegia 15 (2)

not provided (2)

Hereditary spastic paraplegia (1)

not specified (1)

Spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.45

CADD

Uncertain

(source)

DANN

Uncertain

1.0

Eigen

Uncertain

0.27

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.81

MetaRNN

Benign

0.0064

MetaSVM

Benign

-0.95

PhyloP100

5.6

PrimateAI

Benign

0.44

PROVEAN

Benign

-1.8

REVEL

Benign

0.095

Sift

Uncertain

0.012

Sift4G

Uncertain

0.0060

Vest4

0.14

MVP

0.34

MPC

0.18

ClinPred

0.012

GERP RS

4.9

gMVP

0.21

Mutation Taster

=95/5

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

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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