rs76728509

chr14-67754215-G-Achr14-67754215-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_015346.4(ZFYVE26):c.6987-3C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00578 in 1,614,168 control chromosomes in the GnomAD database, including 93 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (41 hom., cov: 32)
  • Exomes 𝑓: 0.0048 (52 hom.)
• Consequence: ZFYVE26 NM_015346.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0001415
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.389

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 14-67754215-G-A is Benign according to our data. Variant chr14-67754215-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 241058.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-67754215-G-A is described in Lovd as [Benign]. Variant chr14-67754215-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0151 (2301/152338) while in subpopulation AFR AF= 0.0432 (1798/41574). AF 95% confidence interval is 0.0416. There are 41 homozygotes in gnomad4. There are 1055 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 41 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZFYVE26	NM_015346.4	c.6987-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000347230.9
ZFYVE26	XM_047431173.1	c.6987-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
ZFYVE26	XM_047431174.1	c.4662-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
ZFYVE26	XM_047431175.1	c.4569-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZFYVE26	ENST00000347230.9	c.6987-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_015346.4	P1

Frequencies

GnomAD3 genomes AF: 0.0151 AC: 2298 AN: 152220 Hom.: 41 Cov.: 32

Gnomad AFR AF: 0.0433

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00766

Gnomad ASJ AF: 0.00951

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00393

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.00395

Gnomad OTH AF: 0.0206

GnomAD3 exomes AF: 0.00683 AC: 1716 AN: 251378 Hom.: 24 AF XY: 0.00619 AC XY: 841 AN XY: 135872

Gnomad AFR exome AF: 0.0445

Gnomad AMR exome AF: 0.00598

Gnomad ASJ exome AF: 0.00982

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00356

Gnomad FIN exome AF: 0.00180

Gnomad NFE exome AF: 0.00426

Gnomad OTH exome AF: 0.00879

GnomAD4 exome AF: 0.00481 AC: 7036 AN: 1461830 Hom.: 52 Cov.: 32 AF XY: 0.00485 AC XY: 3525 AN XY: 727212

Gnomad4 AFR exome AF: 0.0423

Gnomad4 AMR exome AF: 0.00599

Gnomad4 ASJ exome AF: 0.0117

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00436

Gnomad4 FIN exome AF: 0.00146

Gnomad4 NFE exome AF: 0.00358

Gnomad4 OTH exome AF: 0.00775

GnomAD4 genome AF: 0.0151 AC: 2301 AN: 152338 Hom.: 41 Cov.: 32 AF XY: 0.0142 AC XY: 1055 AN XY: 74490

Gnomad4 AFR AF: 0.0432

Gnomad4 AMR AF: 0.00765

Gnomad4 ASJ AF: 0.00951

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00393

Gnomad4 FIN AF: 0.00113

Gnomad4 NFE AF: 0.00395

Gnomad4 OTH AF: 0.0203

Alfa AF: 0.0106 Hom.: 12

Bravo AF: 0.0172

Asia WGS AF: 0.00404 AC: 14 AN: 3478

EpiCase AF: 0.00611

EpiControl AF: 0.00646

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

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. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 18, 2017	- -

Hereditary spastic paraplegia 15 Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
Cadd	Benign	0.23
Dann	Benign	0.66

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00014
dbscSNV1_RF	Benign	0.0020
SpliceAI score (max)		0.10		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: rs76728509; hg19: chr14-68220932;