rs141880939

chr14-67798195-G-Achr14-67798195-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_015346.4(ZFYVE26):c.2067C>T(p.Leu689=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00215 in 1,614,190 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L689L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0022 (14 hom.)
• Consequence: ZFYVE26 NM_015346.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 2.07

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 14-67798195-G-A is Benign according to our data. Variant chr14-67798195-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 193903.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=1, Benign=1}. Variant chr14-67798195-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=2.07 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00165 (251/152304) while in subpopulation NFE AF= 0.00216 (147/68016). AF 95% confidence interval is 0.00188. There are 0 homozygotes in gnomad4. There are 120 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZFYVE26	NM_015346.4	c.2067C>T	p.Leu689=	synonymous_variant	11/42	ENST00000347230.9
ZFYVE26	XM_047431173.1	c.2067C>T	p.Leu689=	synonymous_variant	11/42
ZFYVE26	XM_011536609.3	c.2067C>T	p.Leu689=	synonymous_variant	11/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZFYVE26	ENST00000347230.9	c.2067C>T	p.Leu689=	synonymous_variant	11/42	1	NM_015346.4	P1

Frequencies

GnomAD3 genomes AF: 0.00166 AC: 253 AN: 152186 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.0220

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00207

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00216

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.00233 AC: 585 AN: 251468 Hom.: 3 AF XY: 0.00252 AC XY: 342 AN XY: 135912

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00191

Gnomad ASJ exome AF: 0.00268

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00101

Gnomad FIN exome AF: 0.00203

Gnomad NFE exome AF: 0.00342

Gnomad OTH exome AF: 0.00408

GnomAD4 exome AF: 0.00220 AC: 3222 AN: 1461886 Hom.: 14 Cov.: 39 AF XY: 0.00223 AC XY: 1621 AN XY: 727240

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.00210

Gnomad4 ASJ exome AF: 0.00329

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00126

Gnomad4 FIN exome AF: 0.00232

Gnomad4 NFE exome AF: 0.00238

Gnomad4 OTH exome AF: 0.00245

GnomAD4 genome AF: 0.00165 AC: 251 AN: 152304 Hom.: 0 Cov.: 32 AF XY: 0.00161 AC XY: 120 AN XY: 74474

Gnomad4 AFR AF: 0.000409

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00207

Gnomad4 NFE AF: 0.00216

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00199 Hom.: 0

Bravo AF: 0.00177

EpiCase AF: 0.00289

EpiControl AF: 0.00249

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	ZFYVE26: BP4, BP7, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 02, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 30, 2018	- -

Hereditary spastic paraplegia 15 Uncertain:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Apr 24, 2015

- -

Spastic paraplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
Cadd	Benign	9.4
Dann	Benign	0.64

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs141880939; hg19: chr14-68264912;