rs140540720

chr14-67762343-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP3 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_015346.4(ZFYVE26):c.6229G>A(p.Gly2077Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00135 in 1,614,138 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. G2077G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0070 (10 hom., cov: 33)
  • Exomes 𝑓: 0.00076 (12 hom.)
• Consequence: ZFYVE26 NM_015346.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 7.91

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 -19 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 7: Cadd, Dann, Eigen, FATHMM_MKL, phyloP100way_vertebrate, PrimateAI, PROVEAN [when BayesDel_addAF, max_spliceai, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.011542916).
• BP6: Variant 14-67762343-C-T is Benign according to our data. Variant chr14-67762343-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 241054.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00697 (1061/152256) while in subpopulation AFR AF= 0.0231 (961/41554). AF 95% confidence interval is 0.0219. There are 10 homozygotes in gnomad4. There are 529 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZFYVE26	NM_015346.4	c.6229G>A	p.Gly2077Arg	missense_variant	34/42	ENST00000347230.9
ZFYVE26	XM_047431173.1	c.6229G>A	p.Gly2077Arg	missense_variant	34/42
ZFYVE26	XM_047431174.1	c.3904G>A	p.Gly1302Arg	missense_variant	23/31
ZFYVE26	XM_047431175.1	c.3811G>A	p.Gly1271Arg	missense_variant	23/31

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZFYVE26	ENST00000347230.9	c.6229G>A	p.Gly2077Arg	missense_variant	34/42	1	NM_015346.4	P1

Frequencies

GnomAD3 genomes AF: 0.00697 AC: 1060 AN: 152138 Hom.: 10 Cov.: 33

Gnomad AFR AF: 0.0232

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00452

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.00479

GnomAD3 exomes AF: 0.00172 AC: 432 AN: 251130 Hom.: 5 AF XY: 0.00133 AC XY: 180 AN XY: 135730

Gnomad AFR exome AF: 0.0215

Gnomad AMR exome AF: 0.00156

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000167

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.000761 AC: 1113 AN: 1461882 Hom.: 12 Cov.: 32 AF XY: 0.000650 AC XY: 473 AN XY: 727242

Gnomad4 AFR exome AF: 0.0230

Gnomad4 AMR exome AF: 0.00136

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000151

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000155

Gnomad4 OTH exome AF: 0.00146

GnomAD4 genome AF: 0.00697 AC: 1061 AN: 152256 Hom.: 10 Cov.: 33 AF XY: 0.00711 AC XY: 529 AN XY: 74440

Gnomad4 AFR AF: 0.0231

Gnomad4 AMR AF: 0.00451

Gnomad4 ASJ AF: 0.000289

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000279

Gnomad4 OTH AF: 0.00474

Alfa AF: 0.00129 Hom.: 3

Bravo AF: 0.00771

ESP6500AA AF: 0.0186 AC: 82

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00197 AC: 239

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000178

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary spastic paraplegia 15 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -
Likely benign, 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Spastic paraplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Hereditary spastic paraplegia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jun 01, 2019

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

May 12, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Uncertain	-0.020
Cadd	Pathogenic	28
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.99	D
MetaRNN	Benign	0.012	T;T
MetaSVM	Benign	-0.60	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-7.7	D;D
REVEL	Uncertain	0.45
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.0060	D;D
Polyphen		1.0	.;D
Vest4		0.86
MutPred		0.50		Gain of MoRF binding (P = 0.0134);Gain of MoRF binding (P = 0.0134);
MVP		0.60
MPC		0.75
ClinPred		0.055	T
GERP RS		5.5
gMVP		0.69

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: rs140540720; hg19: chr14-68229060;