rs151166497

Positions:

• chr14-67754144-G-A

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.7055C>T​(p.Thr2352Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00312 in 1,614,242 control chromosomes in the GnomAD database, including 21 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 0.0030 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0031 (19 hom.)
• Consequence: ZFYVE26 NM_015346.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 5.62

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=0.006386131).
• BP6: Variant 14-67754144-G-A is Benign according to our data. Variant chr14-67754144-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 188338.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=4, Uncertain_significance=1}. Variant chr14-67754144-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00305 (464/152348) while in subpopulation NFE AF= 0.00373 (254/68026). AF 95% confidence interval is 0.00336. There are 2 homozygotes in gnomad4. There are 261 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZFYVE26	NM_015346.4	c.7055C>T	p.Thr2352Ile	missense_variant	38/42	ENST00000347230.9	NP_056161.2
ZFYVE26	XM_047431173.1	c.7055C>T	p.Thr2352Ile	missense_variant	38/42		XP_047287129.1
ZFYVE26	XM_047431174.1	c.4730C>T	p.Thr1577Ile	missense_variant	27/31		XP_047287130.1
ZFYVE26	XM_047431175.1	c.4637C>T	p.Thr1546Ile	missense_variant	27/31		XP_047287131.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZFYVE26	ENST00000347230.9	c.7055C>T	p.Thr2352Ile	missense_variant	38/42	1	NM_015346.4	ENSP00000251119	P1

Frequencies

GnomAD3 genomes AF: 0.00305 AC: 464 AN: 152230 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000651

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00229

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.0124

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00373

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00293 AC: 738 AN: 251472 Hom.: 4 AF XY: 0.00304 AC XY: 413 AN XY: 135902

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.00159

Gnomad ASJ exome AF: 0.00218

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00124

Gnomad FIN exome AF: 0.0103

Gnomad NFE exome AF: 0.00327

Gnomad OTH exome AF: 0.00407

GnomAD4 exome AF: 0.00313 AC: 4576 AN: 1461894 Hom.: 19 Cov.: 32 AF XY: 0.00308 AC XY: 2240 AN XY: 727248

Gnomad4 AFR exome AF: 0.000478

Gnomad4 AMR exome AF: 0.00192

Gnomad4 ASJ exome AF: 0.00306

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00107

Gnomad4 FIN exome AF: 0.00932

Gnomad4 NFE exome AF: 0.00326

Gnomad4 OTH exome AF: 0.00265

GnomAD4 genome AF: 0.00305 AC: 464 AN: 152348 Hom.: 2 Cov.: 32 AF XY: 0.00350 AC XY: 261 AN XY: 74500

Gnomad4 AFR AF: 0.000649

Gnomad4 AMR AF: 0.00229

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.0124

Gnomad4 NFE AF: 0.00373

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00333 Hom.: 4

Bravo AF: 0.00273

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00337 AC: 13

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00360 AC: 31

ExAC AF: 0.00255 AC: 310

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00344

EpiControl AF: 0.00332

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary spastic paraplegia 15 Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Nov 12, 2019	- -
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. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 13, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	ZFYVE26: BP4, BS2 -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Dec 06, 2019

- -

Spastic paraplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Hereditary spastic paraplegia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Mar 16, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.45
CADD	Uncertain	24
DANN	Uncertain	1.0
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.81	.;T
MetaRNN	Benign	0.0064	T;T
MetaSVM	Benign	-0.95	T
MutationTaster	Benign	0.95	D;D
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.8	N;N
REVEL	Benign	0.095
Sift	Uncertain	0.012	D;D
Sift4G	Uncertain	0.0060	D;D
Vest4		0.14
MVP		0.34
MPC		0.18
ClinPred		0.012	T
GERP RS		4.9
gMVP		0.21

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: rs151166497; hg19: chr14-68220861;