rs35917338

Positions:

• chr14-67755116-G-A
• chr14-67755116-G-T

Variant summary

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

The ENST00000347230.9(ZFYVE26):​c.6921C>T​(p.Ser2307=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00326 in 1,614,104 control chromosomes in the GnomAD database, including 174 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S2307S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.018 (96 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (78 hom.)
• Consequence: ZFYVE26 ENST00000347230.9 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.534

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 14-67755116-G-A is Benign according to our data. Variant chr14-67755116-G-A is described in ClinVar as [Benign]. Clinvar id is 241057.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.534 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0603 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZFYVE26	NM_015346.4	c.6921C>T	p.Ser2307=	synonymous_variant	37/42	ENST00000347230.9	NP_056161.2
ZFYVE26	XM_047431173.1	c.6921C>T	p.Ser2307=	synonymous_variant	37/42		XP_047287129.1
ZFYVE26	XM_047431174.1	c.4596C>T	p.Ser1532=	synonymous_variant	26/31		XP_047287130.1
ZFYVE26	XM_047431175.1	c.4503C>T	p.Ser1501=	synonymous_variant	26/31		XP_047287131.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZFYVE26	ENST00000347230.9	c.6921C>T	p.Ser2307=	synonymous_variant	37/42	1	NM_015346.4	ENSP00000251119	P1

Frequencies

GnomAD3 genomes AF: 0.0179 AC: 2719 AN: 152102 Hom.: 96 Cov.: 32

Gnomad AFR AF: 0.0621

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00681

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.0115

GnomAD3 exomes AF: 0.00488 AC: 1226 AN: 251456 Hom.: 49 AF XY: 0.00371 AC XY: 504 AN XY: 135896

Gnomad AFR exome AF: 0.0670

Gnomad AMR exome AF: 0.00301

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000217

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000167

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.00173 AC: 2525 AN: 1461884 Hom.: 78 Cov.: 32 AF XY: 0.00148 AC XY: 1075 AN XY: 727242

Gnomad4 AFR exome AF: 0.0609

Gnomad4 AMR exome AF: 0.00358

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000638

Gnomad4 OTH exome AF: 0.00402

GnomAD4 genome AF: 0.0179 AC: 2732 AN: 152220 Hom.: 96 Cov.: 32 AF XY: 0.0171 AC XY: 1269 AN XY: 74424

Gnomad4 AFR AF: 0.0623

Gnomad4 AMR AF: 0.00680

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000279

Gnomad4 OTH AF: 0.0114

Alfa AF: 0.00996 Hom.: 18

Bravo AF: 0.0207

Asia WGS AF: 0.00462 AC: 17 AN: 3476

EpiCase AF: 0.000218

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 19, 2017	- -

Hereditary spastic paraplegia 15 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 24, 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. -

Spastic paraplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Hereditary spastic paraplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

May 29, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	7.8
DANN	Benign	0.69

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

LitVar

Other links and lift over

dbSNP: rs35917338; hg19: chr14-68221833;