rs7156492

chr14-67785952-G-Achr14-67785952-G-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_015346.4(ZFYVE26):c.3210C>T(p.Pro1070=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00134 in 1,614,144 control chromosomes in the GnomAD database, including 27 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. P1070P) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0014 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (25 hom.)
• Consequence: ZFYVE26 NM_015346.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.0830

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.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 14-67785952-G-A is Benign according to our data. Variant chr14-67785952-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 385570.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-67785952-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.083 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00139 (212/152254) while in subpopulation EAS AF= 0.00792 (41/5178). AF 95% confidence interval is 0.00665. There are 2 homozygotes in gnomad4. There are 119 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZFYVE26	NM_015346.4	c.3210C>T	p.Pro1070=	synonymous_variant	18/42	ENST00000347230.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZFYVE26	ENST00000347230.9	c.3210C>T	p.Pro1070=	synonymous_variant	18/42	1	NM_015346.4	P1

Frequencies

GnomAD3 genomes AF: 0.00139 AC: 211 AN: 152136 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00766

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00809

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00292

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00481 AC: 1210 AN: 251408 Hom.: 13 AF XY: 0.00389 AC XY: 528 AN XY: 135866

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.0259

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00837

Gnomad SAS exome AF: 0.000980

Gnomad FIN exome AF: 0.00407

Gnomad NFE exome AF: 0.000202

Gnomad OTH exome AF: 0.00244

GnomAD4 exome AF: 0.00134 AC: 1959 AN: 1461890 Hom.: 25 Cov.: 35 AF XY: 0.00124 AC XY: 902 AN XY: 727246

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.0238

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0110

Gnomad4 SAS exome AF: 0.000869

Gnomad4 FIN exome AF: 0.00401

Gnomad4 NFE exome AF: 0.0000917

Gnomad4 OTH exome AF: 0.000993

GnomAD4 genome AF: 0.00139 AC: 212 AN: 152254 Hom.: 2 Cov.: 32 AF XY: 0.00160 AC XY: 119 AN XY: 74438

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.00778

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00792

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00292

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000518 Hom.: 3

Bravo AF: 0.00254

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

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	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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 26, 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. -

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 13, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
Cadd	Benign	9.0
Dann	Benign	0.65

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: rs7156492; hg19: chr14-68252669; COSMIC: COSV61328966;