rs201771769

Positions:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_015346.4(ZFYVE26):c.7417-5G>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00533 in 1,613,792 control chromosomes in the GnomAD database, including 59 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0038 ( 7 hom., cov: 33)

Exomes 𝑓: 0.0055 ( 52 hom. )

Consequence

ZFYVE26
NM_015346.4 splice_region, intron

Scores

Splicing: ADA: 0.00008164

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: -0.492

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:

ZFYVE26 (HGNC:):

ZFYVE26 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.62).

BP6

Variant 14-67748644-C-G is Benign according to our data. Variant chr14-67748644-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 215520.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1, Benign=3}.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00378 (576/152352) while in subpopulation SAS AF= 0.0207 (100/4826). AF 95% confidence interval is 0.0174. There are 7 homozygotes in gnomad4. There are 293 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE	Protein	UniProt
ZFYVE26	NM_015346.4 linkuse as main transcript	c.7417-5G>C	splice_region_variant, intron_variant	ENST00000347230.9	NP_056161.2	Q68DK2-1
ZFYVE26	XM_047431173.1 linkuse as main transcript	c.7416+2408G>C	intron_variant		XP_047287129.1
ZFYVE26	XM_047431174.1 linkuse as main transcript	c.5092-5G>C	splice_region_variant, intron_variant		XP_047287130.1
ZFYVE26	XM_047431175.1 linkuse as main transcript	c.4999-5G>C	splice_region_variant, intron_variant		XP_047287131.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZFYVE26	ENST00000347230.9 linkuse as main transcript	c.7417-5G>C		splice_region_variant, intron_variant		1	NM_015346.4	ENSP00000251119.5		Q68DK2-1

Frequencies

GnomAD3 genomes

AF:

0.00379

AC:

577

AN:

152234

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000724

Gnomad AMI

AF:

0.0285

Gnomad AMR

AF:

0.00445

Gnomad ASJ

AF:

0.0130

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0207

Gnomad FIN

AF:

0.000941

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.00417

Gnomad OTH

AF:

0.00335

GnomAD3 exomes

AF:

0.00564

AC:

1380

AN:

244894

Hom.:

AF XY:

0.00654

AC XY:

871

AN XY:

133136

show subpopulations

Gnomad AFR exome

AF:

0.00101

Gnomad AMR exome

AF:

0.00386

Gnomad ASJ exome

AF:

0.0101

Gnomad EAS exome

AF:

0.0000547

Gnomad SAS exome

AF:

0.0189

Gnomad FIN exome

AF:

0.00120

Gnomad NFE exome

AF:

0.00458

Gnomad OTH exome

AF:

0.00531

GnomAD4 exome

AF:

0.00549

AC:

8030

AN:

1461440

Hom.:

Cov.:

AF XY:

0.00594

AC XY:

4320

AN XY:

726980

show subpopulations

Gnomad4 AFR exome

AF:

0.000807

Gnomad4 AMR exome

AF:

0.00416

Gnomad4 ASJ exome

AF:

0.00983

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0182

Gnomad4 FIN exome

AF:

0.00141

Gnomad4 NFE exome

AF:

0.00494

Gnomad4 OTH exome

AF:

0.00599

GnomAD4 genome

AF:

0.00378

AC:

576

AN:

152352

Hom.:

Cov.:

AF XY:

0.00393

AC XY:

293

AN XY:

74514

show subpopulations

Gnomad4 AFR

AF:

0.000722

Gnomad4 AMR

AF:

0.00444

Gnomad4 ASJ

AF:

0.0130

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0207

Gnomad4 FIN

AF:

0.000941

Gnomad4 NFE

AF:

0.00417

Gnomad4 OTH

AF:

0.00331

Alfa

AF:

0.00384

Hom.:

Bravo

AF:

0.00363

Asia WGS

AF:

0.00866

AC:

AN:

3478

EpiCase

AF:

0.00622

EpiControl

AF:

0.00611

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 16, 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. -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 21, 2024	- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

May 01, 2016

- -

Spastic paraplegia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Hereditary spastic paraplegia

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jun 13, 2021

- -

Hereditary spastic paraplegia 15

Benign:1

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.62

CADD

Benign

6.4

DANN

Benign

0.76

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000082

dbscSNV1_RF

Benign

0.056

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

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