rs7143196

Positions:

• chr14-67790768-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_015346.4(ZFYVE26):​c.2559G>A​(p.Leu853Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.184 in 1,613,194 control chromosomes in the GnomAD database, including 30,501 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1964 hom., cov: 32)
  • Exomes 𝑓: 0.19 (28537 hom.)
• Consequence: ZFYVE26 NM_015346.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.0140

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 14-67790768-C-T is Benign according to our data. Variant chr14-67790768-C-T is described in ClinVar as [Benign]. Clinvar id is 130777.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-67790768-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.014 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.209 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZFYVE26	NM_015346.4	c.2559G>A	p.Leu853Leu	synonymous_variant	15/42	ENST00000347230.9	NP_056161.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZFYVE26	ENST00000347230.9	c.2559G>A	p.Leu853Leu	synonymous_variant	15/42	1	NM_015346.4	ENSP00000251119.5

Frequencies

GnomAD3 genomes AF: 0.139 AC: 21131 AN: 152092 Hom.: 1965 Cov.: 32

Gnomad AFR AF: 0.0429

Gnomad AMI AF: 0.156

Gnomad AMR AF: 0.101

Gnomad ASJ AF: 0.195

Gnomad EAS AF: 0.0167

Gnomad SAS AF: 0.0644

Gnomad FIN AF: 0.181

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.212

Gnomad OTH AF: 0.125

GnomAD3 exomes AF: 0.145 AC: 36452 AN: 251408 Hom.: 3361 AF XY: 0.147 AC XY: 19997 AN XY: 135876

Gnomad AFR exome AF: 0.0363

Gnomad AMR exome AF: 0.0960

Gnomad ASJ exome AF: 0.193

Gnomad EAS exome AF: 0.0176

Gnomad SAS exome AF: 0.0716

Gnomad FIN exome AF: 0.183

Gnomad NFE exome AF: 0.204

Gnomad OTH exome AF: 0.160

GnomAD4 exome AF: 0.189 AC: 276408 AN: 1460984 Hom.: 28537 Cov.: 33 AF XY: 0.186 AC XY: 135534 AN XY: 726816

Gnomad4 AFR exome AF: 0.0323

Gnomad4 AMR exome AF: 0.0976

Gnomad4 ASJ exome AF: 0.188

Gnomad4 EAS exome AF: 0.0218

Gnomad4 SAS exome AF: 0.0750

Gnomad4 FIN exome AF: 0.187

Gnomad4 NFE exome AF: 0.214

Gnomad4 OTH exome AF: 0.171

GnomAD4 genome AF: 0.139 AC: 21130 AN: 152210 Hom.: 1964 Cov.: 32 AF XY: 0.134 AC XY: 9955 AN XY: 74412

Gnomad4 AFR AF: 0.0428

Gnomad4 AMR AF: 0.101

Gnomad4 ASJ AF: 0.195

Gnomad4 EAS AF: 0.0168

Gnomad4 SAS AF: 0.0655

Gnomad4 FIN AF: 0.181

Gnomad4 NFE AF: 0.211

Gnomad4 OTH AF: 0.124

Alfa AF: 0.187 Hom.: 4618

Bravo AF: 0.128

Asia WGS AF: 0.0450 AC: 157 AN: 3478

EpiCase AF: 0.196

EpiControl AF: 0.194

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 15, 2017	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. -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 24, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Hereditary spastic paraplegia 15 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -

Spastic paraplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Hereditary spastic paraplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 12, 2016

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	5.1
DANN	Benign	0.75

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

LitVar

Other links and lift over

dbSNP: rs7143196; hg19: chr14-68257485; COSMIC: COSV61329350;