rs145183291

chr14-67797664-CA-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_015346.4(ZFYVE26):c.2332+7del variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0155 in 1,613,816 control chromosomes in the GnomAD database, including 355 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.026 (82 hom., cov: 32)
  • Exomes 𝑓: 0.014 (273 hom.)
• Consequence: ZFYVE26 NM_015346.4 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.296

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 -16 ACMG points.

• BP6: Variant 14-67797664-CA-C is Benign according to our data. Variant chr14-67797664-CA-C is described in ClinVar as [Likely_benign]. Clinvar id is 313914.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-67797664-CA-C is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0578 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZFYVE26	NM_015346.4	c.2332+7del		splice_region_variant, intron_variant		ENST00000347230.9
ZFYVE26	XM_011536609.3	c.2332+7del		splice_region_variant, intron_variant
ZFYVE26	XM_047431173.1	c.2332+7del		splice_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZFYVE26	ENST00000347230.9	c.2332+7del		splice_region_variant, intron_variant		1	NM_015346.4	P1

Frequencies

GnomAD3 genomes AF: 0.0255 AC: 3882 AN: 152140 Hom.: 82 Cov.: 32

Gnomad AFR AF: 0.0596

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00968

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.0519

Gnomad SAS AF: 0.0159

Gnomad FIN AF: 0.00726

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0114

Gnomad OTH AF: 0.0230

GnomAD3 exomes AF: 0.0169 AC: 4231 AN: 251080 Hom.: 73 AF XY: 0.0157 AC XY: 2130 AN XY: 135676

Gnomad AFR exome AF: 0.0631

Gnomad AMR exome AF: 0.00535

Gnomad ASJ exome AF: 0.00149

Gnomad EAS exome AF: 0.0514

Gnomad SAS exome AF: 0.0154

Gnomad FIN exome AF: 0.00579

Gnomad NFE exome AF: 0.0123

Gnomad OTH exome AF: 0.0114

GnomAD4 exome AF: 0.0145 AC: 21186 AN: 1461558 Hom.: 273 Cov.: 30 AF XY: 0.0144 AC XY: 10454 AN XY: 727052

Gnomad4 AFR exome AF: 0.0582

Gnomad4 AMR exome AF: 0.00537

Gnomad4 ASJ exome AF: 0.00111

Gnomad4 EAS exome AF: 0.0606

Gnomad4 SAS exome AF: 0.0158

Gnomad4 FIN exome AF: 0.00723

Gnomad4 NFE exome AF: 0.0124

Gnomad4 OTH exome AF: 0.0158

GnomAD4 genome AF: 0.0256 AC: 3896 AN: 152258 Hom.: 82 Cov.: 32 AF XY: 0.0251 AC XY: 1865 AN XY: 74438

Gnomad4 AFR AF: 0.0598

Gnomad4 AMR AF: 0.00960

Gnomad4 ASJ AF: 0.00259

Gnomad4 EAS AF: 0.0522

Gnomad4 SAS AF: 0.0162

Gnomad4 FIN AF: 0.00726

Gnomad4 NFE AF: 0.0114

Gnomad4 OTH AF: 0.0227

Alfa AF: 0.00393 Hom.: 0

Bravo AF: 0.0277

Asia WGS AF: 0.0330 AC: 113 AN: 3478

EpiCase AF: 0.0104

EpiControl AF: 0.0115

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Spastic paraplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 27, 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. -

Hereditary spastic paraplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Nov 11, 2021

- -

Spastic Paraplegia, Recessive Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Sep 30, 2017

- -

Hereditary spastic paraplegia 15 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs145183291; hg19: chr14-68264381;