rs139163400

Positions:

• chr14-67762745-A-G
• chr14-67762745-A-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.6086T>C​(p.Ile2029Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00177 in 1,614,218 control chromosomes in the GnomAD database, including 3 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 0.0013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0018 (3 hom.)
• Consequence: ZFYVE26 NM_015346.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: 9.32

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=0.017748088).
• BP6: Variant 14-67762745-A-G is Benign according to our data. Variant chr14-67762745-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 215890.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, Uncertain_significance=1}. Variant chr14-67762745-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00125 (191/152354) while in subpopulation NFE AF= 0.00201 (137/68028). AF 95% confidence interval is 0.00174. There are 0 homozygotes in gnomad4. There are 85 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZFYVE26	NM_015346.4	c.6086T>C	p.Ile2029Thr	missense_variant	33/42	ENST00000347230.9	NP_056161.2
ZFYVE26	XM_047431173.1	c.6086T>C	p.Ile2029Thr	missense_variant	33/42		XP_047287129.1
ZFYVE26	XM_047431174.1	c.3761T>C	p.Ile1254Thr	missense_variant	22/31		XP_047287130.1
ZFYVE26	XM_047431175.1	c.3668T>C	p.Ile1223Thr	missense_variant	22/31		XP_047287131.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZFYVE26	ENST00000347230.9	c.6086T>C	p.Ile2029Thr	missense_variant	33/42	1	NM_015346.4	ENSP00000251119.5

Frequencies

GnomAD3 genomes AF: 0.00125 AC: 191 AN: 152236 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00226

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00201

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00135 AC: 340 AN: 251358 Hom.: 2 AF XY: 0.00135 AC XY: 183 AN XY: 135850

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.00129

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00407

Gnomad NFE exome AF: 0.00191

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00182 AC: 2661 AN: 1461864 Hom.: 3 Cov.: 32 AF XY: 0.00181 AC XY: 1313 AN XY: 727232

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.000246

Gnomad4 ASJ exome AF: 0.00115

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00367

Gnomad4 NFE exome AF: 0.00208

Gnomad4 OTH exome AF: 0.00159

GnomAD4 genome AF: 0.00125 AC: 191 AN: 152354 Hom.: 0 Cov.: 33 AF XY: 0.00114 AC XY: 85 AN XY: 74500

Gnomad4 AFR AF: 0.000216

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00226

Gnomad4 NFE AF: 0.00201

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00143 Hom.: 0

Bravo AF: 0.00110

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00198 AC: 17

ExAC AF: 0.00147 AC: 179

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00202

EpiControl AF: 0.00160

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 23, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 13, 2021	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 03, 2024	See Variant Classification Assertion Criteria. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	ZFYVE26: 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

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

ZFYVE26-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 01, 2022

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). -

Hereditary spastic paraplegia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 12, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Uncertain	0.040
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	.;T
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	.;D
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.018	T;T
MetaSVM	Benign	-0.89	T
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-1.9	N;N
REVEL	Uncertain	0.44
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.0030	D;D
Polyphen		1.0	.;D
Vest4		0.83
MVP		0.51
MPC		0.73
ClinPred		0.042	T
GERP RS		5.6
gMVP		0.60

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs139163400; hg19: chr14-68229462;