rs34952009

chr14-67767816-C-Achr14-67767816-C-T

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.5678G>T(p.Ser1893Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00821 in 1,614,132 control chromosomes in the GnomAD database, including 71 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1893G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0070 (5 hom., cov: 31)
  • Exomes 𝑓: 0.0083 (66 hom.)
• Consequence: ZFYVE26 NM_015346.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 0.740

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=0.005324453).
• BP6: Variant 14-67767816-C-A is Benign according to our data. Variant chr14-67767816-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 188139.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=5}. Variant chr14-67767816-C-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00701 (1068/152256) while in subpopulation NFE AF= 0.00913 (621/68030). AF 95% confidence interval is 0.00853. There are 5 homozygotes in gnomad4. There are 527 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZFYVE26	NM_015346.4	c.5678G>T	p.Ser1893Ile	missense_variant	31/42	ENST00000347230.9
ZFYVE26	XM_047431173.1	c.5678G>T	p.Ser1893Ile	missense_variant	31/42
ZFYVE26	XM_047431174.1	c.3353G>T	p.Ser1118Ile	missense_variant	20/31
ZFYVE26	XM_047431175.1	c.3260G>T	p.Ser1087Ile	missense_variant	20/31

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZFYVE26	ENST00000347230.9	c.5678G>T	p.Ser1893Ile	missense_variant	31/42	1	NM_015346.4	P1

Frequencies

GnomAD3 genomes AF: 0.00702 AC: 1068 AN: 152138 Hom.: 5 Cov.: 31

Gnomad AFR AF: 0.00152

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.00543

Gnomad ASJ AF: 0.0184

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.0192

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00914

Gnomad OTH AF: 0.00860

GnomAD3 exomes AF: 0.00863 AC: 2170 AN: 251332 Hom.: 15 AF XY: 0.00869 AC XY: 1180 AN XY: 135828

Gnomad AFR exome AF: 0.00148

Gnomad AMR exome AF: 0.00546

Gnomad ASJ exome AF: 0.0181

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00412

Gnomad FIN exome AF: 0.0195

Gnomad NFE exome AF: 0.0102

Gnomad OTH exome AF: 0.0111

GnomAD4 exome AF: 0.00833 AC: 12177 AN: 1461876 Hom.: 66 Cov.: 30 AF XY: 0.00841 AC XY: 6116 AN XY: 727236

Gnomad4 AFR exome AF: 0.00137

Gnomad4 AMR exome AF: 0.00577

Gnomad4 ASJ exome AF: 0.0194

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00385

Gnomad4 FIN exome AF: 0.0191

Gnomad4 NFE exome AF: 0.00849

Gnomad4 OTH exome AF: 0.00863

GnomAD4 genome AF: 0.00701 AC: 1068 AN: 152256 Hom.: 5 Cov.: 31 AF XY: 0.00708 AC XY: 527 AN XY: 74440

Gnomad4 AFR AF: 0.00154

Gnomad4 AMR AF: 0.00543

Gnomad4 ASJ AF: 0.0184

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00187

Gnomad4 FIN AF: 0.0192

Gnomad4 NFE AF: 0.00913

Gnomad4 OTH AF: 0.00851

Alfa AF: 0.00817 Hom.: 2

Bravo AF: 0.00621

TwinsUK AF: 0.00647 AC: 24

ALSPAC AF: 0.00882 AC: 34

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.0105 AC: 90

ExAC AF: 0.00806 AC: 979

Asia WGS AF: 0.00173 AC: 7 AN: 3478

EpiCase AF: 0.00981

EpiControl AF: 0.0104

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 28, 2018	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	ZFYVE26: BP4, BS1, BS2 -

Hereditary spastic paraplegia 15 Uncertain:1

Uncertain significance, 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, 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 31, 2024

- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 08, 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 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jan 21, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.56
Cadd	Benign	16
Dann	Uncertain	0.99
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.34
FATHMM_MKL	Uncertain	0.87	D
MetaRNN	Benign	0.0053	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.89	N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.72	N;N
REVEL	Benign	0.075
Sift	Benign	0.23	T;T
Sift4G	Uncertain	0.046	D;D
Polyphen		0.99	.;D
Vest4		0.29
MVP		0.25
MPC		0.28
ClinPred		0.013	T
GERP RS		1.6
gMVP		0.37

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: rs34952009; hg19: chr14-68234533; COSMIC: COSV61333087;