rs144007962

Positions:

chr14-67755218-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_ModerateBP6BP7BS1BS2

The NM_015346.4(ZFYVE26):c.6819G>A(p.Arg2273=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000652 in 1,614,138 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0032 ( 5 hom., cov: 32)

Exomes 𝑓: 0.00039 ( 3 hom. )

Consequence

ZFYVE26
NM_015346.4 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: -0.109

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 Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.26).

BP6

Variant 14-67755218-C-T is Benign according to our data. Variant chr14-67755218-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 313877.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=2, Uncertain_significance=1}. Variant chr14-67755218-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.109 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00319 (485/152248) while in subpopulation AFR AF= 0.0111 (463/41534). AF 95% confidence interval is 0.0103. There are 5 homozygotes in gnomad4. There are 235 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
ZFYVE26	NM_015346.4 linkuse as main transcript	c.6819G>A	p.Arg2273=	synonymous_variant	37/42	ENST00000347230.9
ZFYVE26	XM_047431173.1 linkuse as main transcript	c.6819G>A	p.Arg2273=	synonymous_variant	37/42
ZFYVE26	XM_047431174.1 linkuse as main transcript	c.4494G>A	p.Arg1498=	synonymous_variant	26/31
ZFYVE26	XM_047431175.1 linkuse as main transcript	c.4401G>A	p.Arg1467=	synonymous_variant	26/31

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZFYVE26	ENST00000347230.9 linkuse as main transcript	c.6819G>A	p.Arg2273=	synonymous_variant	37/42	1	NM_015346.4	P1

Frequencies

GnomAD3 genomes

AF:

0.00318

AC:

484

AN:

152130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0112

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000982

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.000843

AC:

212

AN:

251414

Hom.:

AF XY:

0.000633

AC XY:

AN XY:

135872

show subpopulations

Gnomad AFR exome

AF:

0.0123

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000388

AC:

567

AN:

1461890

Hom.:

Cov.:

AF XY:

0.000340

AC XY:

247

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.0137

Gnomad4 AMR exome

AF:

0.000246

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000927

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000315

Gnomad4 OTH exome

AF:

0.000861

GnomAD4 genome

AF:

0.00319

AC:

485

AN:

152248

Hom.:

Cov.:

AF XY:

0.00316

AC XY:

235

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.0111

Gnomad4 AMR

AF:

0.000981

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00170

Hom.:

Bravo

AF:

0.00394

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary spastic paraplegia 15

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Spastic paraplegia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 27, 2024

- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Jun 19, 2017

- -

Hereditary spastic paraplegia

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Oct 02, 2017

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 16, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.26

CADD

Benign

6.9

DANN

Benign

0.82

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

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