rs75391113

Variant names:

• chr14-67807831-G-A
• rs75391113
• NM_015346.4:c.453C>T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_015346.4(ZFYVE26):​c.453C>T​(p.Ser151Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00242 in 1,613,986 control chromosomes in the GnomAD database, including 138 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0029 (12 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (126 hom.)
• Consequence: ZFYVE26 NM_015346.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.29

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 14-67807831-G-A is Benign according to our data. Variant chr14-67807831-G-A is described in ClinVar as [Benign]. Clinvar id is 313925.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.29 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0673 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZFYVE26	NM_015346.4	c.453C>T	p.Ser151Ser	synonymous_variant	Exon 5 of 42	ENST00000347230.9	NP_056161.2
ZFYVE26	XM_047431173.1	c.453C>T	p.Ser151Ser	synonymous_variant	Exon 5 of 42		XP_047287129.1
ZFYVE26	XM_011536609.3	c.453C>T	p.Ser151Ser	synonymous_variant	Exon 5 of 26		XP_011534911.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZFYVE26	ENST00000347230.9	c.453C>T	p.Ser151Ser	synonymous_variant	Exon 5 of 42	1	NM_015346.4	ENSP00000251119.5

Frequencies

GnomAD3 genomes AF: 0.00290 AC: 441 AN: 152142 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.0732

Gnomad SAS AF: 0.00310

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.00479

GnomAD3 exomes AF: 0.00569 AC: 1428 AN: 250864 Hom.: 57 AF XY: 0.00524 AC XY: 710 AN XY: 135608

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.00120

Gnomad EAS exome AF: 0.0722

Gnomad SAS exome AF: 0.00108

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000221

Gnomad OTH exome AF: 0.00278

GnomAD4 exome AF: 0.00237 AC: 3465 AN: 1461726 Hom.: 126 Cov.: 32 AF XY: 0.00235 AC XY: 1709 AN XY: 727146

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.000201

Gnomad4 ASJ exome AF: 0.00153

Gnomad4 EAS exome AF: 0.0712

Gnomad4 SAS exome AF: 0.00130

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.000192

Gnomad4 OTH exome AF: 0.00414

GnomAD4 genome AF: 0.00290 AC: 441 AN: 152260 Hom.: 12 Cov.: 32 AF XY: 0.00322 AC XY: 240 AN XY: 74432

Gnomad4 AFR AF: 0.000289

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.0734

Gnomad4 SAS AF: 0.00311

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.00474

Alfa AF: 0.000574 Hom.: 0

Bravo AF: 0.00324

Asia WGS AF: 0.0330 AC: 115 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 24, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary spastic paraplegia Benign:1

Nov 18, 2021

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	-0.79
CADD	Benign	1.5
DANN	Benign	0.43
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs75391113; hg19: chr14-68274548; COSMIC: COSV61324584;