rs61746722

chr14-67769603-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_015346.4(ZFYVE26):c.5612G>A(p.Cys1871Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.012 in 1,613,904 control chromosomes in the GnomAD database, including 151 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C1871R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0096 (13 hom., cov: 32)
  • Exomes 𝑓: 0.012 (138 hom.)
• Consequence: ZFYVE26 NM_015346.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.11

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002624333).
• BP6: Variant 14-67769603-C-T is Benign according to our data. Variant chr14-67769603-C-T is described in ClinVar as [Benign]. Clinvar id is 219560.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-67769603-C-T is described in Lovd as [Likely_benign]. Variant chr14-67769603-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00957 (1457/152250) while in subpopulation NFE AF= 0.0151 (1028/68006). AF 95% confidence interval is 0.0143. There are 13 homozygotes in gnomad4. There are 646 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZFYVE26	NM_015346.4	c.5612G>A	p.Cys1871Tyr	missense_variant	29/42	ENST00000347230.9
ZFYVE26	XM_047431173.1	c.5612G>A	p.Cys1871Tyr	missense_variant	29/42
ZFYVE26	XM_047431174.1	c.3287G>A	p.Cys1096Tyr	missense_variant	18/31
ZFYVE26	XM_047431175.1	c.3194G>A	p.Cys1065Tyr	missense_variant	18/31

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZFYVE26	ENST00000347230.9	c.5612G>A	p.Cys1871Tyr	missense_variant	29/42	1	NM_015346.4	P1

Frequencies

GnomAD3 genomes AF: 0.00958 AC: 1457 AN: 152132 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.00270

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00799

Gnomad ASJ AF: 0.0274

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00310

Gnomad FIN AF: 0.00490

Gnomad MID AF: 0.0350

Gnomad NFE AF: 0.0151

Gnomad OTH AF: 0.0100

GnomAD3 exomes AF: 0.00999 AC: 2509 AN: 251074 Hom.: 24 AF XY: 0.0103 AC XY: 1402 AN XY: 135686

Gnomad AFR exome AF: 0.00301

Gnomad AMR exome AF: 0.00645

Gnomad ASJ exome AF: 0.0307

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00340

Gnomad FIN exome AF: 0.00458

Gnomad NFE exome AF: 0.0145

Gnomad OTH exome AF: 0.0135

GnomAD4 exome AF: 0.0122 AC: 17895 AN: 1461654 Hom.: 138 Cov.: 32 AF XY: 0.0123 AC XY: 8933 AN XY: 727136

Gnomad4 AFR exome AF: 0.00215

Gnomad4 AMR exome AF: 0.00742

Gnomad4 ASJ exome AF: 0.0282

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00376

Gnomad4 FIN exome AF: 0.00479

Gnomad4 NFE exome AF: 0.0136

Gnomad4 OTH exome AF: 0.0150

GnomAD4 genome AF: 0.00957 AC: 1457 AN: 152250 Hom.: 13 Cov.: 32 AF XY: 0.00868 AC XY: 646 AN XY: 74454

Gnomad4 AFR AF: 0.00270

Gnomad4 AMR AF: 0.00798

Gnomad4 ASJ AF: 0.0274

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00311

Gnomad4 FIN AF: 0.00490

Gnomad4 NFE AF: 0.0151

Gnomad4 OTH AF: 0.00993

Alfa AF: 0.0145 Hom.: 24

Bravo AF: 0.00967

TwinsUK AF: 0.0116 AC: 43

ALSPAC AF: 0.0130 AC: 50

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.0124 AC: 107

ExAC AF: 0.00961 AC: 1167

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.0158

EpiControl AF: 0.0166

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	ZFYVE26: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 24, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Hereditary spastic paraplegia 15 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

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 06, 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

Nov 17, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.52
Cadd	Benign	10
Dann	Benign	0.29
Eigen	Benign	-1.2
Eigen_PC	Benign	-0.92
FATHMM_MKL	Benign	0.62	D
MetaRNN	Benign	0.0026	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.70	N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	1.6	N;N
REVEL	Benign	0.089
Sift	Benign	1.0	T;T
Sift4G	Benign	0.92	T;T
Polyphen		0.0	.;B
Vest4		0.25
MVP		0.12
MPC		0.28
ClinPred		0.0010	T
GERP RS		0.43
gMVP		0.49

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: rs61746722; hg19: chr14-68236320; COSMIC: COSV100720731;