10-97738626-A-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_001385875.1(ZFYVE27):c.149A>G(p.Tyr50Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000101 in 1,614,182 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000095 ( 0 hom. )

Consequence

ZFYVE27
NM_001385875.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 6.20

Variant links:

Genes affected

ZFYVE27 (HGNC:26559): (zinc finger FYVE-type containing 27) This gene encodes a protein with several transmembrane domains, a Rab11-binding domain and a lipid-binding FYVE finger domain. The encoded protein appears to promote neurite formation. A mutation in this gene has been reported to be associated with hereditary spastic paraplegia, however the pathogenicity of the mutation, which may simply represent a polymorphism, is unclear. [provided by RefSeq, Mar 2010]

ZFYVE27 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2

High AC in GnomAd at 24 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZFYVE27	NM_001385875.1 linkuse as main transcript	c.149A>G	p.Tyr50Cys	missense_variant	2/13	ENST00000684270.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZFYVE27	ENST00000684270.1 linkuse as main transcript	c.149A>G	p.Tyr50Cys	missense_variant	2/13		NM_001385875.1	A1	Q5T4F4-1

Frequencies

GnomAD3 genomes

AF:

0.000158

AC:

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000589

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000398

AC:

AN:

251496

Hom.:

AF XY:

0.0000515

AC XY:

AN XY:

135922

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000615

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.0000951

AC:

139

AN:

1461894

Hom.:

Cov.:

AF XY:

0.0000908

AC XY:

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.000119

Gnomad4 AMR exome

AF:

0.0000894

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000953

Gnomad4 OTH exome

AF:

0.000348

GnomAD4 genome

AF:

0.000158

AC:

AN:

152288

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.000120

Gnomad4 AMR

AF:

0.000588

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000114

Hom.:

Bravo

AF:

0.000230

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Spastic paraplegia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 11, 2022

Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 851871). This missense change has been observed in individual(s) with hereditary spastic paraplegia (PMID: 30564185). This variant is present in population databases (rs199548555, gnomAD 0.006%). This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 50 of the ZFYVE27 protein (p.Tyr50Cys). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Oct 17, 2023

Variant summary: ZFYVE27 c.149A>G (p.Tyr50Cys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 251496 control chromosomes. c.149A>G has been reported in the literature in the heterozygous state in an individual with a clinical diagnosis of Hereditary Spastic Paraplegia who underwent multigene panel testing (D'Amore_2018). This report does not provide unequivocal conclusions about association of the variant with Hereditary Spastic Paraplegia 33. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 30564185). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Both submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Hereditary spastic paraplegia 33

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 15, 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 provided

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The ZFYVE27 p.Tyr50Cys variant was observed in one patient with a clinical diagnosis of spastic paraplegia in a cohort study of 239 Italian patients with spastic paraplegia (freq=0.002) who underwent molecular screening using two NGS panels (D'Amore_2018_PMID:30564185). The variant was not identified in Cosmic or LOVD 3.0 but was identified in dbSNP (ID: rs199548555). The variant was also identified in control databases in 11 of 282898 chromosomes at a frequency of 0.000039 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Latino in 1 of 35440 chromosomes (freq: 0.000028), European (non-Finnish) in 7 of 129196 chromosomes (freq: 0.000054), African in 1 of 24972 chromosomes (freq: 0.00004) and Other in 2 of 7228 chromosomes (freq: 0.000277); it was not observed in the South Asian, European (Finnish), East Asian or Ashkenazi Jewish populations. The variant occurs outside of the splicing consensus sequence and in silico splicing prediction programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, and GeneSplicer) do not predict a greater than 10% difference in splicing. The p.Tyr50 residue is conserved in mammals but not in more distantly related organisms and 5 out of 5 computational analyses programs (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest a high likelihood of impact to the protein. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Uncertain

0.036

BayesDel_noAF

Uncertain

0.0

Cadd

Pathogenic

Dann

Uncertain

1.0

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.94

D;D;D;D;D;D

M_CAP

Benign

0.072

MetaRNN

Uncertain

0.61

D;D;D;D;D;D

MetaSVM

Benign

-0.62

MutationAssessor

Uncertain

2.0

M;M;M;M;M;M

MutationTaster

Benign

1.0

D;D;D;D;D;D;N;N

PrimateAI

Uncertain

0.73

PROVEAN

Uncertain

-3.1

D;N;N;D;.;D

REVEL

Uncertain

0.35

Sift

Uncertain

0.0010

D;D;D;D;.;D

Sift4G

Uncertain

0.0020

D;D;D;D;D;D

Polyphen

1.0, 1.0, 1.0

.;.;D;D;D;D

Vest4

0.87

MVP

0.57

ClinPred

0.58

GERP RS

3.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.7

Varity_R

0.48

gMVP

0.57

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