rs34852231

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_015346.4(ZFYVE26):c.5784T>C(p.Tyr1928Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00582 in 1,614,158 control chromosomes in the GnomAD database, including 94 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.015 ( 42 hom., cov: 31)

Exomes 𝑓: 0.0048 ( 52 hom. )

Consequence

ZFYVE26
NM_015346.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 2.21

Publications

4 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.5).

BP6

Variant 14-67767710-A-G is Benign according to our data. Variant chr14-67767710-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 241053.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=2.21 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0152 (2316/152276) while in subpopulation AFR AF = 0.0436 (1811/41542). AF 95% confidence interval is 0.0419. There are 42 homozygotes in GnomAd4. There are 1061 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 42 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZFYVE26	NM_015346.4 link	c.5784T>C	p.Tyr1928Tyr	synonymous_variant	Exon 31 of 42	ENST00000347230.9	NP_056161.2	Q68DK2-1
ZFYVE26	XM_047431173.1 link	c.5784T>C	p.Tyr1928Tyr	synonymous_variant	Exon 31 of 42		XP_047287129.1
ZFYVE26	XM_047431174.1 link	c.3459T>C	p.Tyr1153Tyr	synonymous_variant	Exon 20 of 31		XP_047287130.1
ZFYVE26	XM_047431175.1 link	c.3366T>C	p.Tyr1122Tyr	synonymous_variant	Exon 20 of 31		XP_047287131.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZFYVE26	ENST00000347230.9 link	c.5784T>C	p.Tyr1928Tyr	synonymous_variant	Exon 31 of 42	1	NM_015346.4	ENSP00000251119.5		Q68DK2-1

Frequencies

GnomAD3 genomes

AF:

0.0152

AC:

2313

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0437

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00773

Gnomad ASJ

AF:

0.00952

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00393

Gnomad FIN

AF:

0.00113

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.00397

Gnomad OTH

AF:

0.0206

GnomAD2 exomes

AF:

0.00686

AC:

1724

AN:

251390

AF XY:

0.00622

show subpopulations

Gnomad AFR exome

AF:

0.0448

Gnomad AMR exome

AF:

0.00598

Gnomad ASJ exome

AF:

0.00982

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00180

Gnomad NFE exome

AF:

0.00428

Gnomad OTH exome

AF:

0.00881

GnomAD4 exome

AF:

0.00484

AC:

7077

AN:

1461882

Hom.:

Cov.:

AF XY:

0.00487

AC XY:

3545

AN XY:

727242

show subpopulations

African (AFR)

AF:

0.0427

AC:

1431

AN:

33480

American (AMR)

AF:

0.00601

AC:

269

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0117

AC:

306

AN:

26134

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39698

South Asian (SAS)

AF:

0.00437

AC:

377

AN:

86258

European-Finnish (FIN)

AF:

0.00146

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.0258

AC:

149

AN:

5768

European-Non Finnish (NFE)

AF:

0.00359

AC:

3989

AN:

1112006

Other (OTH)

AF:

0.00790

AC:

477

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

418

836

1253

1671

2089

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

164

328

492

656

820

<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:

0.0152

AC:

2316

AN:

152276

Hom.:

Cov.:

AF XY:

0.0143

AC XY:

1061

AN XY:

74444

show subpopulations

African (AFR)

AF:

0.0436

AC:

1811

AN:

41542

American (AMR)

AF:

0.00772

AC:

118

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00952

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00394

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00113

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.0340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00397

AC:

270

AN:

68032

Other (OTH)

AF:

0.0204

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

110

220

330

440

550

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

<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:

0.00868

Hom.:

Bravo

AF:

0.0173

Asia WGS

AF:

0.00433

AC:

AN:

3478

EpiCase

AF:

0.00616

EpiControl

AF:

0.00646

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Oct 18, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Hereditary spastic paraplegia 15

Benign:2

Dec 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not specified

Benign:1

Oct 11, 2017

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. -

Spastic paraplegia

Benign:1

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary spastic paraplegia

Benign:1

Sep 01, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.50

CADD

Benign

4.5

(source)

DANN

Benign

0.53

PhyloP100

2.2

Mutation Taster

=99/1

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over