chr14-67805304-C-A

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.1184G>T(p.Gly395Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00339 in 1,614,068 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G395G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0027 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0035 ( 21 hom. )

Consequence

ZFYVE26
NM_015346.4 missense, splice_region

Scores

Splicing: ADA: 0.00004754

Clinical Significance

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

Conservation

PhyloP100: 1.48

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=0.0025664866).

BP6

Variant 14-67805304-C-A is Benign according to our data. Variant chr14-67805304-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 188381.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00271 (413/152276) while in subpopulation SAS AF = 0.00706 (34/4814). AF 95% confidence interval is 0.00519. There are 1 homozygotes in GnomAd4. There are 212 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 21 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.1184G>T	p.Gly395Val	missense splice_region	Exon 8 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.1184G>T	p.Gly395Val	missense splice_region	Exon 8 of 42	ENSP00000251119.5	Q68DK2-1
ZFYVE26	ENST00000555452.1	TSL:1	c.1184G>T	p.Gly395Val	missense splice_region	Exon 8 of 35	ENSP00000450603.1	G3V2D8
ZFYVE26	ENST00000554523.5	TSL:1	n.1321G>T		splice_region non_coding_transcript_exon	Exon 8 of 41

Frequencies

GnomAD3 genomes

AF:

0.00271

AC:

413

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000700

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00452

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00706

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00385

Gnomad OTH

AF:

0.00670

GnomAD2 exomes

AF:

0.00343

AC:

860

AN:

251044

AF XY:

0.00411

show subpopulations

Gnomad AFR exome

AF:

0.000678

Gnomad AMR exome

AF:

0.00180

Gnomad ASJ exome

AF:

0.00109

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.000508

Gnomad NFE exome

AF:

0.00426

Gnomad OTH exome

AF:

0.00326

GnomAD4 exome

AF:

0.00346

AC:

5051

AN:

1461792

Hom.:

Cov.:

AF XY:

0.00371

AC XY:

2695

AN XY:

727186

show subpopulations

African (AFR)

AF:

0.000627

AC:

AN:

33480

American (AMR)

AF:

0.00224

AC:

100

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00184

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00899

AC:

775

AN:

86230

European-Finnish (FIN)

AF:

0.000505

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00334

AC:

3710

AN:

1111964

Other (OTH)

AF:

0.00450

AC:

272

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

296

591

887

1182

1478

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

128

256

384

512

640

<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:

0.00271

AC:

413

AN:

152276

Hom.:

Cov.:

AF XY:

0.00285

AC XY:

212

AN XY:

74452

show subpopulations

African (AFR)

AF:

0.000698

AC:

AN:

41556

American (AMR)

AF:

0.00451

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00706

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00385

AC:

262

AN:

68028

Other (OTH)

AF:

0.00664

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

116

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:

0.00346

Hom.:

Bravo

AF:

0.00297

TwinsUK

AF:

0.00351

AC:

ALSPAC

AF:

0.00363

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.00337

AC:

ExAC

AF:

0.00364

AC:

442

Asia WGS

AF:

0.00289

AC:

AN:

3478

EpiCase

AF:

0.00502

EpiControl

AF:

0.00617

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Hereditary spastic paraplegia (1)

Hereditary spastic paraplegia 15 (1)

not specified (1)

Spastic paraplegia (1)

ZFYVE26-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.096

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.55

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.0072

Eigen

Benign

-0.51

Eigen_PC

Benign

-0.30

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.39

M_CAP

Benign

0.015

MetaRNN

Benign

0.0026

MetaSVM

Benign

-1.1

PhyloP100

1.5

PrimateAI

Benign

0.40

PROVEAN

Benign

-0.13

REVEL

Benign

0.055

Sift

Benign

0.22

Sift4G

Uncertain

0.011

Polyphen

0.045

Vest4

0.17

MVP

0.23

MPC

0.21

ClinPred

0.0083

GERP RS

4.8

gMVP

0.16

Mutation Taster

=88/12

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000048

dbscSNV1_RF

Benign

0.0

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