rs771906344

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5

The NM_015346.4(ZFYVE26):c.5791-6G>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,611,808 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

ZFYVE26
NM_015346.4 splice_region, splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.9998

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:2

Conservation

PhyloP100: -0.312

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 14-67766453-C-T is Pathogenic according to our data. Variant chr14-67766453-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 555081.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=2, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE
ZFYVE26	NM_015346.4 linkuse as main transcript	c.5791-6G>A	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant	ENST00000347230.9
ZFYVE26	XM_047431173.1 linkuse as main transcript	c.5791-6G>A	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
ZFYVE26	XM_047431174.1 linkuse as main transcript	c.3466-6G>A	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
ZFYVE26	XM_047431175.1 linkuse as main transcript	c.3373-6G>A	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZFYVE26	ENST00000347230.9 linkuse as main transcript	c.5791-6G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_015346.4	P1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152106

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000240

AC:

AN:

249544

Hom.:

AF XY:

0.0000296

AC XY:

AN XY:

135006

show subpopulations

Gnomad AFR exome

AF:

0.000124

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000178

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000480

AC:

AN:

1459702

Hom.:

Cov.:

AF XY:

0.00000551

AC XY:

AN XY:

726130

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152106

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74286

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000494

Hom.:

Bravo

AF:

0.0000151

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary spastic paraplegia 15

Pathogenic:1Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 30, 2023	Variant summary: ZFYVE26 c.5791-6G>A alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes the canonical 3' acceptor site and two predict the variant weakens the canonical 3' acceptor site. Four predict the variant creates a cryptic 3' acceptor site. At least one publication reports experimental evidence that this variant affects mRNA splicing and results in a frameshift of the encoded protein (Goizet_2009). The variant allele was found at a frequency of 2.4e-05 in 249544 control chromosomes (gnomAD). c.5791-6G>A has been reported in the literature in an individual affected with Hereditary Spastic Paraplegia (example: Goizet_2009). The following publication has been ascertained in the context of this evaluation (PMID: 19805727). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=2) and pathogenic/likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Nov 16, 2021	NM_015346.3(ZFYVE26):c.5791-6G>A is an intronic variant classified as a variant of uncertain significance in the context of spastic paraplegia type 15. c.5791-6G>A has been observed in cases with relevant disease (PMID: 19805727). Functional assessments of this variant are available in the literature (PMID: 19805727). c.5791-6G>A has been observed in population frequency databases (gnomAD: AFR 0.01%). In summary, there is insufficient evidence to classify NM_015346.3(ZFYVE26):c.5791-6G>A as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening. -

Spastic paraplegia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jul 12, 2023

This sequence change falls in intron 31 of the ZFYVE26 gene. It does not directly change the encoded amino acid sequence of the ZFYVE26 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in activation of a cryptic splice site and introduces a premature termination codon (PMID: 19805727). The resulting mRNA is expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 555081). This variant has been observed in individual(s) with hereditary spastic paraplegia (PMID: 19805727). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs771906344, gnomAD 0.01%). -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Oct 23, 2020

- -

Hereditary spastic paraplegia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 12, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.69

Cadd

Benign

Dann

Benign

0.74

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.97

SpliceAI score (max)

0.99

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.99

Position offset: -2

DS_AL_spliceai

0.24

Position offset: -6

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over