chr14-67748470-G-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.7586C>G(p.Pro2529Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000908 in 1,612,892 control chromosomes in the GnomAD database, including 15 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. P2529L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0047 ( 8 hom., cov: 33)

Exomes 𝑓: 0.00051 ( 7 hom. )

Consequence

ZFYVE26
NM_015346.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.368

Publications

0 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=0.0026982427).

BP6

Variant 14-67748470-G-C is Benign according to our data. Variant chr14-67748470-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 313873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00475 (723/152358) while in subpopulation AFR AF = 0.0162 (675/41580). AF 95% confidence interval is 0.0152. There are 8 homozygotes in GnomAd4. There are 353 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 8 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.7586C>G	p.Pro2529Arg	missense	Exon 42 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.7586C>G	p.Pro2529Arg	missense	Exon 42 of 42	ENSP00000251119.5	Q68DK2-1
ZFYVE26	ENST00000554523.5	TSL:1	n.8341C>G		non_coding_transcript_exon	Exon 41 of 41
ZFYVE26	ENST00000554557.5	TSL:1	n.*5564C>G		non_coding_transcript_exon	Exon 40 of 40	ENSP00000450431.1	G3V230

Frequencies

GnomAD3 genomes

AF:

0.00473

AC:

720

AN:

152240

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0162

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00183

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:

0.000147

Gnomad OTH

AF:

0.00430

GnomAD2 exomes

AF:

0.00119

AC:

297

AN:

249500

AF XY:

0.000874

show subpopulations

Gnomad AFR exome

AF:

0.0149

Gnomad AMR exome

AF:

0.00110

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000107

Gnomad OTH exome

AF:

0.000656

GnomAD4 exome

AF:

0.000507

AC:

741

AN:

1460534

Hom.:

Cov.:

AF XY:

0.000435

AC XY:

316

AN XY:

726570

show subpopulations

African (AFR)

AF:

0.0144

AC:

482

AN:

33440

American (AMR)

AF:

0.00127

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000464

AC:

AN:

86206

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53280

Middle Eastern (MID)

AF:

0.00162

AC:

AN:

4942

European-Non Finnish (NFE)

AF:

0.000106

AC:

118

AN:

1111846

Other (OTH)

AF:

0.00119

AC:

AN:

60270

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

102

153

204

255

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.00475

AC:

723

AN:

152358

Hom.:

Cov.:

AF XY:

0.00474

AC XY:

353

AN XY:

74496

show subpopulations

African (AFR)

AF:

0.0162

AC:

675

AN:

41580

American (AMR)

AF:

0.00183

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000147

AC:

AN:

68038

Other (OTH)

AF:

0.00426

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

112

149

186

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:

0.000425

Hom.:

Bravo

AF:

0.00510

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.0129

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00138

AC:

167

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

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 provided (2)

Hereditary spastic paraplegia (1)

Spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.74

CADD

Benign

(source)

DANN

Benign

0.92

Eigen

Benign

-0.93

Eigen_PC

Benign

-0.86

FATHMM_MKL

Benign

0.24

MetaRNN

Benign

0.0027

MetaSVM

Benign

-1.0

PhyloP100

0.37

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.23

REVEL

Benign

0.062

Sift

Benign

0.16

Sift4G

Uncertain

0.023

Vest4

0.077

MVP

0.061

MPC

0.17

ClinPred

0.0034

GERP RS

0.027

gMVP

0.071

Mutation Taster

=99/1

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