rs17104689

Positions:

• chr14-67805264-C-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_015346.4(ZFYVE26):​c.1224G>T​(p.Gly408Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.017 in 1,614,060 control chromosomes in the GnomAD database, including 546 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.033 (192 hom., cov: 33)
  • Exomes 𝑓: 0.015 (354 hom.)
• Consequence: ZFYVE26 NM_015346.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.0170

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.24).
• BP6: Variant 14-67805264-C-A is Benign according to our data. Variant chr14-67805264-C-A is described in ClinVar as [Benign]. Clinvar id is 130776.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.017 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0843 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZFYVE26	NM_015346.4	c.1224G>T	p.Gly408Gly	synonymous_variant	8/42	ENST00000347230.9	NP_056161.2
ZFYVE26	XM_047431173.1	c.1224G>T	p.Gly408Gly	synonymous_variant	8/42		XP_047287129.1
ZFYVE26	XM_011536609.3	c.1224G>T	p.Gly408Gly	synonymous_variant	8/26		XP_011534911.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZFYVE26	ENST00000347230.9	c.1224G>T	p.Gly408Gly	synonymous_variant	8/42	1	NM_015346.4	ENSP00000251119.5

Frequencies

GnomAD3 genomes AF: 0.0331 AC: 5041 AN: 152188 Hom.: 191 Cov.: 33

Gnomad AFR AF: 0.0863

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0123

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.0522

Gnomad SAS AF: 0.0159

Gnomad FIN AF: 0.00725

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0115

Gnomad OTH AF: 0.0263

GnomAD3 exomes AF: 0.0186 AC: 4670 AN: 250946 Hom.: 99 AF XY: 0.0170 AC XY: 2301 AN XY: 135684

Gnomad AFR exome AF: 0.0894

Gnomad AMR exome AF: 0.00599

Gnomad ASJ exome AF: 0.00149

Gnomad EAS exome AF: 0.0510

Gnomad SAS exome AF: 0.0153

Gnomad FIN exome AF: 0.00573

Gnomad NFE exome AF: 0.0123

Gnomad OTH exome AF: 0.0131

GnomAD4 exome AF: 0.0153 AC: 22337 AN: 1461754 Hom.: 354 Cov.: 32 AF XY: 0.0150 AC XY: 10932 AN XY: 727178

Gnomad4 AFR exome AF: 0.0850

Gnomad4 AMR exome AF: 0.00637

Gnomad4 ASJ exome AF: 0.00111

Gnomad4 EAS exome AF: 0.0603

Gnomad4 SAS exome AF: 0.0158

Gnomad4 FIN exome AF: 0.00721

Gnomad4 NFE exome AF: 0.0125

Gnomad4 OTH exome AF: 0.0177

GnomAD4 genome AF: 0.0333 AC: 5069 AN: 152306 Hom.: 192 Cov.: 33 AF XY: 0.0322 AC XY: 2401 AN XY: 74474

Gnomad4 AFR AF: 0.0866

Gnomad4 AMR AF: 0.0123

Gnomad4 ASJ AF: 0.00259

Gnomad4 EAS AF: 0.0525

Gnomad4 SAS AF: 0.0164

Gnomad4 FIN AF: 0.00725

Gnomad4 NFE AF: 0.0115

Gnomad4 OTH AF: 0.0260

Alfa AF: 0.0209 Hom.: 62

Bravo AF: 0.0369

Asia WGS AF: 0.0340 AC: 119 AN: 3478

EpiCase AF: 0.0104

EpiControl AF: 0.0117

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 25, 2016	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. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 30, 2017	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

Nov 11, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.24
CADD	Benign	9.0
DANN	Benign	0.68
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs17104689; hg19: chr14-68271981;