rs138965635

Positions:

• chr14-67772130-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_015346.4(ZFYVE26):​c.5401G>A​(p.Ala1801Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000722 in 1,613,106 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00055 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00074 (0 hom.)
• Consequence: ZFYVE26 NM_015346.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5 B:2 O:1
• Conservation: PhyloP100: 4.95

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.02182737).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZFYVE26	NM_015346.4	c.5401G>A	p.Ala1801Thr	missense_variant	28/42	ENST00000347230.9	NP_056161.2
ZFYVE26	XM_047431173.1	c.5401G>A	p.Ala1801Thr	missense_variant	28/42		XP_047287129.1
ZFYVE26	XM_047431174.1	c.3076G>A	p.Ala1026Thr	missense_variant	17/31		XP_047287130.1
ZFYVE26	XM_047431175.1	c.2983G>A	p.Ala995Thr	missense_variant	17/31		XP_047287131.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZFYVE26	ENST00000347230.9	c.5401G>A	p.Ala1801Thr	missense_variant	28/42	1	NM_015346.4	ENSP00000251119.5

Frequencies

GnomAD3 genomes AF: 0.000546 AC: 83 AN: 152048 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000787

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000956

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.000377 AC: 94 AN: 249342 Hom.: 0 AF XY: 0.000379 AC XY: 51 AN XY: 134668

Gnomad AFR exome AF: 0.000186

Gnomad AMR exome AF: 0.000175

Gnomad ASJ exome AF: 0.000299

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000710

Gnomad OTH exome AF: 0.000329

GnomAD4 exome AF: 0.000740 AC: 1081 AN: 1460940 Hom.: 0 Cov.: 32 AF XY: 0.000694 AC XY: 504 AN XY: 726674

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000915

Gnomad4 OTH exome AF: 0.000663

GnomAD4 genome AF: 0.000545 AC: 83 AN: 152166 Hom.: 0 Cov.: 32 AF XY: 0.000511 AC XY: 38 AN XY: 74380

Gnomad4 AFR AF: 0.0000963

Gnomad4 AMR AF: 0.000786

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000956

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.000777 Hom.: 0

Bravo AF: 0.000544

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.000305 AC: 37

EpiCase AF: 0.000763

EpiControl AF: 0.000953

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5 Benign:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary spastic paraplegia 15 Uncertain:2 Other:1

not provided, no classification provided	phenotyping only	GenomeConnect - Invitae Patient Insights Network	-	Variant interpreted as Uncertain significance and reported on 12-16-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 16, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Dec 16, 2021	- -

not provided Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 24, 2022	BP4 -
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	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Spastic paraplegia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 05, 2022

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1801 of the ZFYVE26 protein (p.Ala1801Thr). This variant is present in population databases (rs138965635, gnomAD 0.07%). This variant has not been reported in the literature in individuals affected with ZFYVE26-related conditions. ClinVar contains an entry for this variant (Variation ID: 241050). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Mar 26, 2024

Variant summary: ZFYVE26 c.5401G>A (p.Ala1801Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00038 in 249342 control chromosomes. This frequency does not allow conclusion about variant significance. To our knowledge, no occurrence of c.5401G>A in individuals affected with Hereditary Spastic Paraplegia 15 and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 241050). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.015	.;T
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.017
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	.;D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.022	T;T
MetaSVM	Benign	-1.1	T
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.48	N;N
REVEL	Benign	0.027
Sift	Benign	0.18	T;T
Sift4G	Uncertain	0.050	T;T
Polyphen		0.29	.;B
Vest4		0.28
MVP		0.15
MPC		0.35
ClinPred		0.089	T
GERP RS		3.9
gMVP		0.14

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs138965635; hg19: chr14-68238847;