14-67798418-G-A

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.1844C>T(p.Ser615Phe) variant causes a missense change. The variant allele was found at a frequency of 0.0109 in 1,613,474 control chromosomes in the GnomAD database, including 138 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0088 ( 11 hom., cov: 32)

Exomes 𝑓: 0.011 ( 127 hom. )

Consequence

ZFYVE26
NM_015346.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 5.20

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), Orphanet, Myriad Women’s Health, G2P

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=0.005330801).

BP6

Variant 14-67798418-G-A is Benign according to our data. Variant chr14-67798418-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 219559.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 = 0.00884 (1346/152238) while in subpopulation NFE AF = 0.0139 (945/68028). AF 95% confidence interval is 0.0132. There are 11 homozygotes in GnomAd4. There are 606 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZFYVE26	NM_015346.4 link	c.1844C>T	p.Ser615Phe	missense_variant	Exon 11 of 42	ENST00000347230.9	NP_056161.2	Q68DK2-1
ZFYVE26	XM_047431173.1 link	c.1844C>T	p.Ser615Phe	missense_variant	Exon 11 of 42		XP_047287129.1
ZFYVE26	XM_011536609.3 link	c.1844C>T	p.Ser615Phe	missense_variant	Exon 11 of 26		XP_011534911.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZFYVE26	ENST00000347230.9 link	c.1844C>T	p.Ser615Phe	missense_variant	Exon 11 of 42	1	NM_015346.4	ENSP00000251119.5		Q68DK2-1

Frequencies

GnomAD3 genomes

AF:

0.00886

AC:

1348

AN:

152122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00239

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00694

Gnomad ASJ

AF:

0.0268

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00436

Gnomad FIN

AF:

0.00538

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.0139

Gnomad OTH

AF:

0.00764

GnomAD2 exomes

AF:

0.00927

AC:

2328

AN:

251238

AF XY:

0.00944

show subpopulations

Gnomad AFR exome

AF:

0.00277

Gnomad AMR exome

AF:

0.00527

Gnomad ASJ exome

AF:

0.0286

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00481

Gnomad NFE exome

AF:

0.0134

Gnomad OTH exome

AF:

0.0131

GnomAD4 exome

AF:

0.0111

AC:

16249

AN:

1461236

Hom.:

127

Cov.:

AF XY:

0.0112

AC XY:

8147

AN XY:

726808

show subpopulations

African (AFR)

AF:

0.00212

AC:

AN:

33448

American (AMR)

AF:

0.00642

AC:

287

AN:

44686

Ashkenazi Jewish (ASJ)

AF:

0.0261

AC:

682

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39680

South Asian (SAS)

AF:

0.00395

AC:

341

AN:

86250

European-Finnish (FIN)

AF:

0.00483

AC:

258

AN:

53410

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.0124

AC:

13742

AN:

1111504

Other (OTH)

AF:

0.0128

AC:

770

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

987

1974

2960

3947

4934

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00884

AC:

1346

AN:

152238

Hom.:

Cov.:

AF XY:

0.00814

AC XY:

606

AN XY:

74432

show subpopulations

African (AFR)

AF:

0.00238

AC:

AN:

41522

American (AMR)

AF:

0.00693

AC:

106

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0268

AC:

AN:

3468

East Asian (EAS)

AF:

0.000193

AC:

AN:

5184

South Asian (SAS)

AF:

0.00436

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00538

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.0274

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0139

AC:

945

AN:

68028

Other (OTH)

AF:

0.00756

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

133

200

266

333

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0124

Hom.:

Bravo

AF:

0.00863

TwinsUK

AF:

0.0113

AC:

ALSPAC

AF:

0.0119

AC:

ESP6500AA

AF:

0.00250

AC:

ESP6500EA

AF:

0.0122

AC:

105

ExAC

AF:

0.00892

AC:

1083

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.0154

EpiControl

AF:

0.0154

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Dec 26, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ZFYVE26: BP4, BS1, BS2 -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Hereditary spastic paraplegia 15

Benign:2

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Dec 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Spastic paraplegia

Benign:1

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Jul 06, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Hereditary spastic paraplegia

Benign:1

Oct 29, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.36

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.041

.;T

Eigen

Uncertain

0.66

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.83

.;T

MetaRNN

Benign

0.0053

T;T

MetaSVM

Benign

-0.84

PhyloP100

5.2

PrimateAI

Benign

0.46

PROVEAN

Benign

-0.56

N;N

REVEL

Benign

0.14

Sift

Benign

0.086

T;D

Sift4G

Uncertain

0.017

D;D

Polyphen

0.98

.;D

Vest4

0.46

MVP

0.40

MPC

0.70

ClinPred

0.025

GERP RS

5.7

gMVP

0.41

Mutation Taster

=92/8

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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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14-67798418-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over