rs193074768

chr14-67753745-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_015346.4(ZFYVE26):c.7150G>A(p.Val2384Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000744 in 1,613,658 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. V2384V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00024 (1 hom., cov: 32)
  • Exomes 𝑓: 0.000057 (1 hom.)
• Consequence: ZFYVE26 NM_015346.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.07

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 Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.017398804).
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000236 (36/152276) while in subpopulation AMR AF= 0.0019 (29/15300). AF 95% confidence interval is 0.00136. There are 1 homozygotes in gnomad4. There are 17 alleles in male gnomad4 subpopulation. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZFYVE26	NM_015346.4	c.7150G>A	p.Val2384Ile	missense_variant	39/42	ENST00000347230.9
ZFYVE26	XM_047431173.1	c.7150G>A	p.Val2384Ile	missense_variant	39/42
ZFYVE26	XM_047431174.1	c.4825G>A	p.Val1609Ile	missense_variant	28/31
ZFYVE26	XM_047431175.1	c.4732G>A	p.Val1578Ile	missense_variant	28/31

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZFYVE26	ENST00000347230.9	c.7150G>A	p.Val2384Ile	missense_variant	39/42	1	NM_015346.4	P1

Frequencies

GnomAD3 genomes AF: 0.000237 AC: 36 AN: 152158 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

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: 0.0000735

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000959 AC: 24 AN: 250366 Hom.: 0 AF XY: 0.0000813 AC XY: 11 AN XY: 135312

Gnomad AFR exome AF: 0.0000622

Gnomad AMR exome AF: 0.000319

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000164

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000618

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000575 AC: 84 AN: 1461382 Hom.: 1 Cov.: 31 AF XY: 0.0000592 AC XY: 43 AN XY: 726938

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000537

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000139

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000261

Gnomad4 OTH exome AF: 0.000149

GnomAD4 genome AF: 0.000236 AC: 36 AN: 152276 Hom.: 1 Cov.: 32 AF XY: 0.000228 AC XY: 17 AN XY: 74470

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.00190

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000559 Hom.: 0

Bravo AF: 0.000325

ExAC AF: 0.0000494 AC: 6

EpiCase AF: 0.000273

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Spastic paraplegia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 17, 2022

This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 2384 of the ZFYVE26 protein (p.Val2384Ile). This variant is present in population databases (rs193074768, gnomAD 0.04%). 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: 220542). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 14, 2021

The c.7150G>A (p.V2384I) alteration is located in exon 39 (coding exon 38) of the ZFYVE26 gene. This alteration results from a G to A substitution at nucleotide position 7150, causing the valine (V) at amino acid position 2384 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.43
Cadd	Benign	18
Dann	Benign	0.77
Eigen	Benign	-0.23
Eigen_PC	Benign	0.026
FATHMM_MKL	Uncertain	0.91	D
M_CAP	Benign	0.0024	T
MetaRNN	Benign	0.017	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.93	D;D
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	0.20	N;N
REVEL	Benign	0.077
Sift	Benign	0.66	T;T
Sift4G	Benign	0.58	T;T
Vest4		0.33
MVP		0.13
MPC		0.21
ClinPred		0.038	T
GERP RS		5.4
gMVP		0.12

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: rs193074768; hg19: chr14-68220462;