rs116890187

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.2887G>C(p.Val963Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00743 in 1,614,220 control chromosomes in the GnomAD database, including 57 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0061 ( 7 hom., cov: 33)

Exomes 𝑓: 0.0076 ( 50 hom. )

Consequence

ZFYVE26
NM_015346.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:8

Conservation

PhyloP100: 2.75

Publications

13 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=0.006394297).

BP6

Variant 14-67789467-C-G is Benign according to our data. Variant chr14-67789467-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 188323.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00614 (936/152346) while in subpopulation AMR AF = 0.00824 (126/15298). AF 95% confidence interval is 0.00754. There are 7 homozygotes in GnomAd4. There are 446 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 7 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.2887G>C	p.Val963Leu	missense	Exon 16 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.2887G>C	p.Val963Leu	missense	Exon 16 of 42	ENSP00000251119.5	Q68DK2-1
ZFYVE26	ENST00000555452.1	TSL:1	c.2887G>C	p.Val963Leu	missense	Exon 16 of 35	ENSP00000450603.1	G3V2D8
ZFYVE26	ENST00000554523.5	TSL:1	n.3024G>C		non_coding_transcript_exon	Exon 16 of 41

Frequencies

GnomAD3 genomes

AF:

0.00614

AC:

935

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00150

Gnomad AMI

AF:

0.00768

Gnomad AMR

AF:

0.00825

Gnomad ASJ

AF:

0.0288

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00682

Gnomad FIN

AF:

0.00348

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.00810

Gnomad OTH

AF:

0.00622

GnomAD2 exomes

AF:

0.00774

AC:

1943

AN:

251010

AF XY:

0.00783

show subpopulations

Gnomad AFR exome

AF:

0.00204

Gnomad AMR exome

AF:

0.00792

Gnomad ASJ exome

AF:

0.0314

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00296

Gnomad NFE exome

AF:

0.00871

Gnomad OTH exome

AF:

0.0129

GnomAD4 exome

AF:

0.00756

AC:

11052

AN:

1461874

Hom.:

Cov.:

AF XY:

0.00759

AC XY:

5519

AN XY:

727236

show subpopulations

African (AFR)

AF:

0.00140

AC:

AN:

33480

American (AMR)

AF:

0.00854

AC:

382

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0312

AC:

816

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00588

AC:

507

AN:

86258

European-Finnish (FIN)

AF:

0.00303

AC:

162

AN:

53400

Middle Eastern (MID)

AF:

0.0101

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00769

AC:

8549

AN:

1112012

Other (OTH)

AF:

0.00879

AC:

531

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

767

1534

2301

3068

3835

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

320

640

960

1280

1600

<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:

0.00614

AC:

936

AN:

152346

Hom.:

Cov.:

AF XY:

0.00599

AC XY:

446

AN XY:

74498

show subpopulations

African (AFR)

AF:

0.00149

AC:

AN:

41578

American (AMR)

AF:

0.00824

AC:

126

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0288

AC:

100

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5188

South Asian (SAS)

AF:

0.00703

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00348

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00810

AC:

551

AN:

68032

Other (OTH)

AF:

0.00616

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

149

198

248

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:

0.00950

Hom.:

Bravo

AF:

0.00662

TwinsUK

AF:

0.00593

AC:

ALSPAC

AF:

0.00830

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.00953

AC:

ExAC

AF:

0.00761

AC:

924

Asia WGS

AF:

0.00289

AC:

AN:

3478

EpiCase

AF:

0.00894

EpiControl

AF:

0.0102

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

not specified (2)

Hereditary spastic paraplegia (1)

Hereditary spastic paraplegia 15 (1)

Spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.0084

Eigen

Benign

0.083

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.84

MetaRNN

Benign

0.0064

MetaSVM

Benign

-1.1

PhyloP100

2.7

PrimateAI

Benign

0.44

PROVEAN

Benign

-0.20

REVEL

Benign

0.040

Sift

Benign

0.25

Sift4G

Benign

0.15

Polyphen

0.32

Vest4

0.28

MVP

0.20

MPC

0.29

ClinPred

0.0049

GERP RS

4.7

gMVP

0.30

Mutation Taster

=94/6

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