chr14-67798329-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_015346.4(ZFYVE26):c.1933A>G(p.Met645Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00168 in 1,613,450 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 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. M645I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0016 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0017 ( 31 hom. )

Consequence

ZFYVE26
NM_015346.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -1.38

Publications

10 publications found

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 Gene-Disease associations (from GenCC):

hereditary spastic paraplegia 15
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet, Myriad Women’s Health

ZFYVE26 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0025982857).

BP6

Variant 14-67798329-T-C is Benign according to our data. Variant chr14-67798329-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 385569.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00163 (249/152304) while in subpopulation EAS AF = 0.0133 (69/5186). AF 95% confidence interval is 0.0108. There are 3 homozygotes in GnomAd4. There are 146 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015346.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZFYVE26	NM_015346.4	MANE Select	c.1933A>G	p.Met645Val	missense	Exon 11 of 42	NP_056161.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ZFYVE26	ENST00000347230.9	TSL:1 MANE Select	c.1933A>G	p.Met645Val	missense	Exon 11 of 42	ENSP00000251119.5	Q68DK2-1
ZFYVE26	ENST00000555452.1	TSL:1	c.1933A>G	p.Met645Val	missense	Exon 11 of 35	ENSP00000450603.1	G3V2D8
ZFYVE26	ENST00000554523.5	TSL:1	n.2070A>G		non_coding_transcript_exon	Exon 11 of 41

Frequencies

GnomAD3 genomes

AF:

0.00163

AC:

248

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00779

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0135

Gnomad SAS

AF:

0.00103

Gnomad FIN

AF:

0.00292

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000206

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.00537

AC:

1345

AN:

250618

AF XY:

0.00440

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.0261

Gnomad ASJ exome

AF:

0.000100

Gnomad EAS exome

AF:

0.0152

Gnomad FIN exome

AF:

0.00408

Gnomad NFE exome

AF:

0.000238

Gnomad OTH exome

AF:

0.00278

GnomAD4 exome

AF:

0.00169

AC:

2463

AN:

1461146

Hom.:

Cov.:

AF XY:

0.00157

AC XY:

1142

AN XY:

726910

show subpopulations

African (AFR)

AF:

0.000150

AC:

AN:

33400

American (AMR)

AF:

0.0240

AC:

1069

AN:

44618

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26084

East Asian (EAS)

AF:

0.0203

AC:

806

AN:

39698

South Asian (SAS)

AF:

0.000917

AC:

AN:

86196

European-Finnish (FIN)

AF:

0.00401

AC:

214

AN:

53394

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000191

AC:

212

AN:

1111662

Other (OTH)

AF:

0.00124

AC:

AN:

60328

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

168

337

505

674

842

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

108

144

180

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00163

AC:

249

AN:

152304

Hom.:

Cov.:

AF XY:

0.00196

AC XY:

146

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.000144

AC:

AN:

41562

American (AMR)

AF:

0.00791

AC:

121

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.0133

AC:

AN:

5186

South Asian (SAS)

AF:

0.00104

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00292

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000206

AC:

AN:

68016

Other (OTH)

AF:

0.00142

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00134

Hom.:

Bravo

AF:

0.00281

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00453

AC:

550

Asia WGS

AF:

0.00866

AC:

AN:

3478

EpiCase

AF:

0.000327

EpiControl

AF:

0.000119

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hereditary spastic paraplegia 15 (2)

not specified (2)

Hereditary spastic paraplegia (1)

not provided (1)

Spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.057

BayesDel_addAF

Benign

-0.75

BayesDel_noAF

Benign

-0.83

CADD

Benign

0.0040

(source)

DANN

Benign

0.50

DEOGEN2

Benign

0.0080

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.10

LIST_S2

Benign

0.40

MetaRNN

Benign

0.0026

MetaSVM

Benign

-1.0

PhyloP100

-1.4

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.69

REVEL

Benign

0.029

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.024

MVP

0.072

MPC

0.16

ClinPred

0.0026

GERP RS

-10

gMVP

0.12

Mutation Taster

=98/2

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over