14-67785952-G-C

Variant names:

• chr14-67785952-G-C
• rs7156492
• NM_015346.4:c.3210C>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_015346.4(ZFYVE26):​c.3210C>G​(p.Pro1070Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0219 in 1,614,134 control chromosomes in the GnomAD database, including 844 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P1070P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.045 (315 hom., cov: 32)
  • Exomes 𝑓: 0.019 (529 hom.)
• Consequence: ZFYVE26 NM_015346.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.0830
• Publications: 7 publications found

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]

ZFYVE26 Gene-Disease associations (from GenCC):

• hereditary spastic paraplegia 15

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Myriad Women’s Health, G2P

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 14-67785952-G-C is Benign according to our data. Variant chr14-67785952-G-C is described in ClinVar as Benign. ClinVar VariationId is 130779.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.083 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.118 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZFYVE26	NM_015346.4	c.3210C>G	p.Pro1070Pro	synonymous_variant	Exon 18 of 42	ENST00000347230.9	NP_056161.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZFYVE26	ENST00000347230.9	c.3210C>G	p.Pro1070Pro	synonymous_variant	Exon 18 of 42	1	NM_015346.4	ENSP00000251119.5

Frequencies

GnomAD3 genomes AF: 0.0454 AC: 6914 AN: 152126 Hom.: 315 Cov.: 32

Gnomad AFR AF: 0.121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0196

Gnomad ASJ AF: 0.0115

Gnomad EAS AF: 0.0519

Gnomad SAS AF: 0.0195

Gnomad FIN AF: 0.00895

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0150

Gnomad OTH AF: 0.0420

GnomAD2 exomes AF: 0.0246 AC: 6182 AN: 251408 AF XY: 0.0228

Gnomad AFR exome AF: 0.127

Gnomad AMR exome AF: 0.0111

Gnomad ASJ exome AF: 0.0106

Gnomad EAS exome AF: 0.0518

Gnomad FIN exome AF: 0.00804

Gnomad NFE exome AF: 0.0161

Gnomad OTH exome AF: 0.0196

GnomAD4 exome AF: 0.0195 AC: 28494 AN: 1461890 Hom.: 529 Cov.: 35 AF XY: 0.0192 AC XY: 13996 AN XY: 727246

African (AFR) AF: 0.119 AC: 3999 AN: 33480

American (AMR) AF: 0.0114 AC: 509 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0114 AC: 299 AN: 26136

East Asian (EAS) AF: 0.0602 AC: 2389 AN: 39700

South Asian (SAS) AF: 0.0194 AC: 1670 AN: 86258

European-Finnish (FIN) AF: 0.00929 AC: 496 AN: 53416

Middle Eastern (MID) AF: 0.0368 AC: 212 AN: 5768

European-Non Finnish (NFE) AF: 0.0157 AC: 17482 AN: 1112012

Other (OTH) AF: 0.0238 AC: 1438 AN: 60396

GnomAD4 genome AF: 0.0455 AC: 6927 AN: 152244 Hom.: 315 Cov.: 32 AF XY: 0.0441 AC XY: 3280 AN XY: 74432

African (AFR) AF: 0.121 AC: 5005 AN: 41526

American (AMR) AF: 0.0196 AC: 299 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0115 AC: 40 AN: 3472

East Asian (EAS) AF: 0.0522 AC: 270 AN: 5176

South Asian (SAS) AF: 0.0197 AC: 95 AN: 4826

European-Finnish (FIN) AF: 0.00895 AC: 95 AN: 10612

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0150 AC: 1023 AN: 68016

Other (OTH) AF: 0.0416 AC: 88 AN: 2116

Alfa AF: 0.00821 Hom.: 3

Bravo AF: 0.0507

EpiCase AF: 0.0159

EpiControl AF: 0.0180

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

May 25, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

not provided Benign:2

Sep 30, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Hereditary spastic paraplegia 15 Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Spastic paraplegia Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary spastic paraplegia Benign:1

Dec 12, 2016

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	8.1
DANN	Benign	0.71
PhyloP100		0.083
Mutation Taster		=97/3	polymorphism (auto)

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

Other links and lift over

dbSNP: rs7156492; hg19: chr14-68252669; COSMIC: COSV61325750;