rs147919567

Positions:

• chr14-67807607-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.677G>A​(p.Arg226His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00114 in 1,614,204 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 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 0.0015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (6 hom.)
• Consequence: ZFYVE26 NM_015346.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 B:9
• Conservation: PhyloP100: -0.691

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005218923).
• BP6: Variant 14-67807607-C-T is Benign according to our data. Variant chr14-67807607-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 313924.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=1, Benign=1, Likely_pathogenic=1}. Variant chr14-67807607-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00154 (235/152326) while in subpopulation AMR AF= 0.00366 (56/15306). AF 95% confidence interval is 0.00289. There are 0 homozygotes in gnomad4. There are 139 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZFYVE26	NM_015346.4	c.677G>A	p.Arg226His	missense_variant	5/42	ENST00000347230.9	NP_056161.2
ZFYVE26	XM_047431173.1	c.677G>A	p.Arg226His	missense_variant	5/42		XP_047287129.1
ZFYVE26	XM_011536609.3	c.677G>A	p.Arg226His	missense_variant	5/26		XP_011534911.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZFYVE26	ENST00000347230.9	c.677G>A	p.Arg226His	missense_variant	5/42	1	NM_015346.4	ENSP00000251119.5

Frequencies

GnomAD3 genomes AF: 0.00154 AC: 235 AN: 152208 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00118

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00366

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.00116

Gnomad OTH AF: 0.00621

GnomAD3 exomes AF: 0.00170 AC: 428 AN: 251266 Hom.: 3 AF XY: 0.00169 AC XY: 230 AN XY: 135874

Gnomad AFR exome AF: 0.00105

Gnomad AMR exome AF: 0.00364

Gnomad ASJ exome AF: 0.00606

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00127

Gnomad FIN exome AF: 0.000277

Gnomad NFE exome AF: 0.00130

Gnomad OTH exome AF: 0.00489

GnomAD4 exome AF: 0.00110 AC: 1612 AN: 1461878 Hom.: 6 Cov.: 32 AF XY: 0.00116 AC XY: 844 AN XY: 727240

Gnomad4 AFR exome AF: 0.000836

Gnomad4 AMR exome AF: 0.00353

Gnomad4 ASJ exome AF: 0.00562

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00173

Gnomad4 FIN exome AF: 0.000337

Gnomad4 NFE exome AF: 0.000866

Gnomad4 OTH exome AF: 0.00205

GnomAD4 genome AF: 0.00154 AC: 235 AN: 152326 Hom.: 0 Cov.: 32 AF XY: 0.00187 AC XY: 139 AN XY: 74490

Gnomad4 AFR AF: 0.00118

Gnomad4 AMR AF: 0.00366

Gnomad4 ASJ AF: 0.00634

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00116

Gnomad4 OTH AF: 0.00615

Alfa AF: 0.00137 Hom.: 0

Bravo AF: 0.00167

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00116 AC: 10

ExAC AF: 0.00162 AC: 197

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00185

EpiControl AF: 0.00207

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1 Benign:9

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	ZFYVE26: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 19, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 13, 2023	Variant summary: ZFYVE26 c.677G>A (p.Arg226His) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0017 in 251266 control chromosomes in the gnomAD database, including 3 homozygotes. The relatively high allele frequency and the homozygous occurrences, suggest that the variant might be a benign polymorphism. The variant, c.677G>A, has been reported in the literature in heterozygous state in an individual with clinical suspicion of hereditary spastic paraplegia (Burguez_2017). This report does not provide unequivocal conclusions about association of the variant with Hereditary Spastic Paraplegia 15. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six submitters have provided clinical-significance assessments for this variant in ClinVar after 2014, mostly without evidence for independent evaluation, and classified the variant as VUS (n=2), likely benign (n=3) / benign (n=1). Based on the evidence outlined above, the variant was classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 29, 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. -

Tip-toe gait Pathogenic:1

Likely pathogenic, flagged submission

clinical testing

Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino

-

Hereditary motor sensory neuropathy (HMSN), also known as Charcot-Marie-Tooth Disease (CMT), is the most commonly inherited peripheral polyneuropathy. It constitutes a group of inherited, progressive, motor and sensory peripheral nerve disorders with properties of demyelination, axonal degeneration, or both. It is classified by clinical characteristics, modes of inheritance, electrophysiologic features, metabolic defects, and specific gene markers. Our patients all walk on tiptoe, so they show similar symptoms. When we genetically test them with our toe walking panel, we find that around 90 per cent of them have a genetic variant that explains their toe walking. These can be assigned, for example, to the area of myopathies (such as variants of the COL6A3 gene), the area of hereditary neuropathies (such as variants of the KMT2C gene) or the area of metabolic diseases (such as variants of the PYGM gene). In a smaller group of patients with almost identical symptoms, no abnormality is found in the genes of our panel, but spastic paraplegia can be detected. In another small group of our toe walkers, no abnormalities can be detected in the genes analysed in our toe walking panel, nor do they suffer from spastic paraplegia, as is also the case with healthy children. In contrast to these, however, they show a tiptoe gait. These patients suffer from infantile cerebral palsy, in which toe walking can also be observed. -

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. -

ZFYVE26-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 18, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Spastic paraplegia Benign:1

Likely 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

Jan 01, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	6.6
DANN	Benign	0.93
DEOGEN2	Benign	0.0059	.;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.98
FATHMM_MKL	Benign	0.050	N
LIST_S2	Benign	0.71	.;T
M_CAP	Benign	0.0095	T
MetaRNN	Benign	0.0052	T;T
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.24	N;N
REVEL	Benign	0.042
Sift	Benign	0.60	T;T
Sift4G	Benign	0.58	T;T
Polyphen		0.0030	.;B
Vest4		0.081
MVP		0.040
MPC		0.20
ClinPred		0.0068	T
GERP RS		-1.1
gMVP		0.11

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs147919567; hg19: chr14-68274324; COSMIC: COSV99052078;