rs34296097

Positions:

• chr14-67783395-G-A

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.3757C>T​(p.Leu1253=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00956 in 1,614,152 control chromosomes in the GnomAD database, including 479 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.033 (219 hom., cov: 32)
  • Exomes 𝑓: 0.0071 (260 hom.)
• Consequence: ZFYVE26 NM_015346.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.916

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 14-67783395-G-A is Benign according to our data. Variant chr14-67783395-G-A is described in ClinVar as [Benign]. Clinvar id is 313905.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-67783395-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.916 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0985 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZFYVE26	NM_015346.4	c.3757C>T	p.Leu1253=	synonymous_variant	21/42	ENST00000347230.9	NP_056161.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZFYVE26	ENST00000347230.9	c.3757C>T	p.Leu1253=	synonymous_variant	21/42	1	NM_015346.4	ENSP00000251119	P1

Frequencies

GnomAD3 genomes AF: 0.0327 AC: 4980 AN: 152148 Hom.: 215 Cov.: 32

Gnomad AFR AF: 0.101

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0198

Gnomad ASJ AF: 0.0196

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00311

Gnomad FIN AF: 0.000376

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.00459

Gnomad OTH AF: 0.0435

GnomAD3 exomes AF: 0.0127 AC: 3186 AN: 251326 Hom.: 109 AF XY: 0.0106 AC XY: 1435 AN XY: 135832

Gnomad AFR exome AF: 0.105

Gnomad AMR exome AF: 0.0151

Gnomad ASJ exome AF: 0.0196

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00405

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00466

Gnomad OTH exome AF: 0.0158

GnomAD4 exome AF: 0.00713 AC: 10428 AN: 1461886 Hom.: 260 Cov.: 34 AF XY: 0.00681 AC XY: 4953 AN XY: 727242

Gnomad4 AFR exome AF: 0.112

Gnomad4 AMR exome AF: 0.0164

Gnomad4 ASJ exome AF: 0.0196

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00390

Gnomad4 FIN exome AF: 0.0000936

Gnomad4 NFE exome AF: 0.00376

Gnomad4 OTH exome AF: 0.0132

GnomAD4 genome AF: 0.0329 AC: 5008 AN: 152266 Hom.: 219 Cov.: 32 AF XY: 0.0316 AC XY: 2350 AN XY: 74452

Gnomad4 AFR AF: 0.101

Gnomad4 AMR AF: 0.0197

Gnomad4 ASJ AF: 0.0196

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00311

Gnomad4 FIN AF: 0.000376

Gnomad4 NFE AF: 0.00459

Gnomad4 OTH AF: 0.0430

Alfa AF: 0.0173 Hom.: 46

Bravo AF: 0.0378

Asia WGS AF: 0.00866 AC: 30 AN: 3478

EpiCase AF: 0.00812

EpiControl AF: 0.00634

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 01, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 26, 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. -

Hereditary spastic paraplegia 15 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -
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. -

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

Oct 29, 2021

- -

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	-0.83
CADD	Benign	2.3
DANN	Benign	0.38

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: rs34296097; hg19: chr14-68250112;