rs34852231

Positions:

• chr14-67767710-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_015346.4(ZFYVE26):​c.5784T>C​(p.Tyr1928=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00582 in 1,614,158 control chromosomes in the GnomAD database, including 94 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (42 hom., cov: 31)
  • Exomes 𝑓: 0.0048 (52 hom.)
• Consequence: ZFYVE26 NM_015346.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 2.21

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=-0.5).
• BP6: Variant 14-67767710-A-G is Benign according to our data. Variant chr14-67767710-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 241053.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.21 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0152 (2316/152276) while in subpopulation AFR AF= 0.0436 (1811/41542). AF 95% confidence interval is 0.0419. There are 42 homozygotes in gnomad4. There are 1061 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 42 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZFYVE26	NM_015346.4	c.5784T>C	p.Tyr1928=	synonymous_variant	31/42	ENST00000347230.9
ZFYVE26	XM_047431173.1	c.5784T>C	p.Tyr1928=	synonymous_variant	31/42
ZFYVE26	XM_047431174.1	c.3459T>C	p.Tyr1153=	synonymous_variant	20/31
ZFYVE26	XM_047431175.1	c.3366T>C	p.Tyr1122=	synonymous_variant	20/31

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZFYVE26	ENST00000347230.9	c.5784T>C	p.Tyr1928=	synonymous_variant	31/42	1	NM_015346.4	P1

Frequencies

GnomAD3 genomes AF: 0.0152 AC: 2313 AN: 152158 Hom.: 42 Cov.: 31

Gnomad AFR AF: 0.0437

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00773

Gnomad ASJ AF: 0.00952

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00393

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.00397

Gnomad OTH AF: 0.0206

GnomAD3 exomes AF: 0.00686 AC: 1724 AN: 251390 Hom.: 24 AF XY: 0.00622 AC XY: 845 AN XY: 135864

Gnomad AFR exome AF: 0.0448

Gnomad AMR exome AF: 0.00598

Gnomad ASJ exome AF: 0.00982

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00356

Gnomad FIN exome AF: 0.00180

Gnomad NFE exome AF: 0.00428

Gnomad OTH exome AF: 0.00881

GnomAD4 exome AF: 0.00484 AC: 7077 AN: 1461882 Hom.: 52 Cov.: 30 AF XY: 0.00487 AC XY: 3545 AN XY: 727242

Gnomad4 AFR exome AF: 0.0427

Gnomad4 AMR exome AF: 0.00601

Gnomad4 ASJ exome AF: 0.0117

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00437

Gnomad4 FIN exome AF: 0.00146

Gnomad4 NFE exome AF: 0.00359

Gnomad4 OTH exome AF: 0.00790

GnomAD4 genome AF: 0.0152 AC: 2316 AN: 152276 Hom.: 42 Cov.: 31 AF XY: 0.0143 AC XY: 1061 AN XY: 74444

Gnomad4 AFR AF: 0.0436

Gnomad4 AMR AF: 0.00772

Gnomad4 ASJ AF: 0.00952

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00394

Gnomad4 FIN AF: 0.00113

Gnomad4 NFE AF: 0.00397

Gnomad4 OTH AF: 0.0204

Alfa AF: 0.00700 Hom.: 21

Bravo AF: 0.0173

Asia WGS AF: 0.00433 AC: 15 AN: 3478

EpiCase AF: 0.00616

EpiControl AF: 0.00646

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

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	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 11, 2017

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

Sep 01, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Oct 18, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	4.5
DANN	Benign	0.53

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: rs34852231; hg19: chr14-68234427;