rs34373049

Positions:

chr14-67752483-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000347230.9(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
ENST00000347230.9 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 2.54

Variant links:

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]

ZFYVE26 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 104 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
ZFYVE26	NM_015346.4 linkuse as main transcript	c.7232G>A	p.Arg2411His	missense_variant	40/42	ENST00000347230.9	NP_056161.2
ZFYVE26	XM_047431173.1 linkuse as main transcript	c.7232G>A	p.Arg2411His	missense_variant	40/42		XP_047287129.1
ZFYVE26	XM_047431174.1 linkuse as main transcript	c.4907G>A	p.Arg1636His	missense_variant	29/31		XP_047287130.1
ZFYVE26	XM_047431175.1 linkuse as main transcript	c.4814G>A	p.Arg1605His	missense_variant	29/31		XP_047287131.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZFYVE26	ENST00000347230.9 linkuse as main transcript	c.7232G>A	p.Arg2411His	missense_variant	40/42	1	NM_015346.4	ENSP00000251119	P1

Frequencies

GnomAD3 genomes

AF:

0.0297

AC:

4521

AN:

152088

Hom.:

105

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.0376

AC XY:

27346

AN XY:

727234

show subpopulations

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.:

AF XY:

0.0307

AC XY:

2288

AN XY:

74414

show subpopulations

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.:

Bravo

AF:

0.0241

TwinsUK

AF:

0.0437

AC:

162

ALSPAC

AF:

0.0480

AC:

185

ESP6500AA

AF:

0.0132

AC:

ESP6500EA

AF:

0.0402

AC:

346

ExAC

AF:

0.0291

AC:

3537

Asia WGS

AF:

0.00491

AC:

AN:

3478

EpiCase

AF:

0.0381

EpiControl

AF:

0.0378

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 01, 2017	- -
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. -

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

Labcorp Genetics (formerly Invitae), Labcorp

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

BayesDel_noAF

Benign

-0.41

CADD

Benign

DANN

Uncertain

1.0

Eigen

Benign

0.16

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Benign

0.72

LIST_S2

Benign

0.83

.;T

MetaRNN

Benign

0.0029

T;T

MetaSVM

Benign

-1.1

MutationTaster

Benign

0.76

D;N

PrimateAI

Benign

0.25

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over