rs34373049

chr14-67752483-C-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.7232G>A(p.Arg2411His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0376 in 1,614,066 control chromosomes in the GnomAD database, including 1,399 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2411C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.030 (104 hom., cov: 32)
  • Exomes 𝑓: 0.038 (1295 hom.)
• Consequence: ZFYVE26 NM_015346.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 2.54

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 (MetaRNN=0.0029006302).
• BP6: Variant 14-67752483-C-T is Benign according to our data. Variant chr14-67752483-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 220663.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-67752483-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0297 (4523/152206) while in subpopulation NFE AF= 0.0435 (2958/67996). AF 95% confidence interval is 0.0422. There are 104 homozygotes in gnomad4. There are 2288 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 105 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZFYVE26	NM_015346.4	c.7232G>A	p.Arg2411His	missense_variant	40/42	ENST00000347230.9
ZFYVE26	XM_047431173.1	c.7232G>A	p.Arg2411His	missense_variant	40/42
ZFYVE26	XM_047431174.1	c.4907G>A	p.Arg1636His	missense_variant	29/31
ZFYVE26	XM_047431175.1	c.4814G>A	p.Arg1605His	missense_variant	29/31

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZFYVE26	ENST00000347230.9	c.7232G>A	p.Arg2411His	missense_variant	40/42	1	NM_015346.4	P1

Frequencies

GnomAD3 genomes AF: 0.0297 AC: 4521 AN: 152088 Hom.: 105 Cov.: 32

Gnomad AFR AF: 0.00811

Gnomad AMI AF: 0.0319

Gnomad AMR AF: 0.0178

Gnomad ASJ AF: 0.0133

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0114

Gnomad FIN AF: 0.0722

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0435

Gnomad OTH AF: 0.0254

GnomAD3 exomes AF: 0.0301 AC: 7568 AN: 251372 Hom.: 164 AF XY: 0.0305 AC XY: 4144 AN XY: 135858

Gnomad AFR exome AF: 0.00843

Gnomad AMR exome AF: 0.0156

Gnomad ASJ exome AF: 0.0105

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0115

Gnomad FIN exome AF: 0.0712

Gnomad NFE exome AF: 0.0410

Gnomad OTH exome AF: 0.0380

GnomAD4 exome AF: 0.0384 AC: 56208 AN: 1461860 Hom.: 1295 Cov.: 32 AF XY: 0.0376 AC XY: 27346 AN XY: 727234

Gnomad4 AFR exome AF: 0.00562

Gnomad4 AMR exome AF: 0.0152

Gnomad4 ASJ exome AF: 0.0113

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0117

Gnomad4 FIN exome AF: 0.0726

Gnomad4 NFE exome AF: 0.0434

Gnomad4 OTH exome AF: 0.0306

GnomAD4 genome AF: 0.0297 AC: 4523 AN: 152206 Hom.: 104 Cov.: 32 AF XY: 0.0307 AC XY: 2288 AN XY: 74414

Gnomad4 AFR AF: 0.00809

Gnomad4 AMR AF: 0.0178

Gnomad4 ASJ AF: 0.0133

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0124

Gnomad4 FIN AF: 0.0722

Gnomad4 NFE AF: 0.0435

Gnomad4 OTH AF: 0.0251

Alfa AF: 0.0355 Hom.: 66

Bravo AF: 0.0241

TwinsUK AF: 0.0437 AC: 162

ALSPAC AF: 0.0480 AC: 185

ESP6500AA AF: 0.0132 AC: 58

ESP6500EA AF: 0.0402 AC: 346

ExAC AF: 0.0291 AC: 3537

Asia WGS AF: 0.00491 AC: 17 AN: 3478

EpiCase AF: 0.0381

EpiControl AF: 0.0378

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	Apr 13, 2016	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, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 01, 2017	- -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Hereditary spastic paraplegia 15 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Spastic paraplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Hereditary spastic paraplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 18, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.41
Cadd	Benign	22
Dann	Uncertain	1.0
Eigen	Benign	0.16
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Benign	0.72	D
MetaRNN	Benign	0.0029	T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.76	D;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.77	N;N
REVEL	Benign	0.056
Sift	Benign	0.14	T;D
Sift4G	Uncertain	0.0080	D;D
Vest4		0.28
MPC		0.66
ClinPred		0.024	T
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.15

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: rs34373049; hg19: chr14-68219200;