rs116890187

Positions:

• chr14-67789467-C-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_015346.4(ZFYVE26):​c.2887G>C​(p.Val963Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00743 in 1,614,220 control chromosomes in the GnomAD database, including 57 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0061 (7 hom., cov: 33)
  • Exomes 𝑓: 0.0076 (50 hom.)
• Consequence: ZFYVE26 NM_015346.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: 2.75

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006394297).
• BP6: Variant 14-67789467-C-G is Benign according to our data. Variant chr14-67789467-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 188323.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=4, Uncertain_significance=1}. Variant chr14-67789467-C-G is described in Lovd as [Benign]. Variant chr14-67789467-C-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00614 (936/152346) while in subpopulation AMR AF= 0.00824 (126/15298). AF 95% confidence interval is 0.00754. There are 7 homozygotes in gnomad4. There are 446 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	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZFYVE26	NM_015346.4	c.2887G>C	p.Val963Leu	missense_variant	16/42	ENST00000347230.9	NP_056161.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZFYVE26	ENST00000347230.9	c.2887G>C	p.Val963Leu	missense_variant	16/42	1	NM_015346.4	ENSP00000251119	P1

Frequencies

GnomAD3 genomes AF: 0.00614 AC: 935 AN: 152228 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.00150

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.00825

Gnomad ASJ AF: 0.0288

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00682

Gnomad FIN AF: 0.00348

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00810

Gnomad OTH AF: 0.00622

GnomAD3 exomes AF: 0.00774 AC: 1943 AN: 251010 Hom.: 5 AF XY: 0.00783 AC XY: 1063 AN XY: 135696

Gnomad AFR exome AF: 0.00204

Gnomad AMR exome AF: 0.00792

Gnomad ASJ exome AF: 0.0314

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00618

Gnomad FIN exome AF: 0.00296

Gnomad NFE exome AF: 0.00871

Gnomad OTH exome AF: 0.0129

GnomAD4 exome AF: 0.00756 AC: 11052 AN: 1461874 Hom.: 50 Cov.: 31 AF XY: 0.00759 AC XY: 5519 AN XY: 727236

Gnomad4 AFR exome AF: 0.00140

Gnomad4 AMR exome AF: 0.00854

Gnomad4 ASJ exome AF: 0.0312

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00588

Gnomad4 FIN exome AF: 0.00303

Gnomad4 NFE exome AF: 0.00769

Gnomad4 OTH exome AF: 0.00879

GnomAD4 genome AF: 0.00614 AC: 936 AN: 152346 Hom.: 7 Cov.: 33 AF XY: 0.00599 AC XY: 446 AN XY: 74498

Gnomad4 AFR AF: 0.00149

Gnomad4 AMR AF: 0.00824

Gnomad4 ASJ AF: 0.0288

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00703

Gnomad4 FIN AF: 0.00348

Gnomad4 NFE AF: 0.00810

Gnomad4 OTH AF: 0.00616

Alfa AF: 0.00950 Hom.: 7

Bravo AF: 0.00662

TwinsUK AF: 0.00593 AC: 22

ALSPAC AF: 0.00830 AC: 32

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00953 AC: 82

ExAC AF: 0.00761 AC: 924

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.00894

EpiControl AF: 0.0102

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	ZFYVE26: BP4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Aug 01, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 01, 2017	- -

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 28, 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 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

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

Sep 09, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0084	.;T
Eigen	Benign	0.083
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.84	.;T
MetaRNN	Benign	0.0064	T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.95	D;D
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.20	N;N
REVEL	Benign	0.040
Sift	Benign	0.25	T;T
Sift4G	Benign	0.15	T;T
Polyphen		0.32	.;B
Vest4		0.28
MVP		0.20
MPC		0.29
ClinPred		0.0049	T
GERP RS		4.7
gMVP		0.30

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: rs116890187; hg19: chr14-68256184;