rs34373049

Variant names:

Your query was ambiguous. Multiple possible variants found:

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.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. 13/19 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. 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

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.54

Publications

8 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=0.0029006302).

BP6

Variant 14-67752483-C-T is Benign according to our data. Variant chr14-67752483-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 220663.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 104 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.7232G>A	p.Arg2411His	missense	Exon 40 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.7232G>A	p.Arg2411His	missense	Exon 40 of 42	ENSP00000251119.5	Q68DK2-1
ZFYVE26	ENST00000557306.1	TSL:1	c.770G>A	p.Arg257His	missense	Exon 6 of 7	ENSP00000452142.1	A0A2H2FF08
ZFYVE26	ENST00000554523.5	TSL:1	n.7987G>A		non_coding_transcript_exon	Exon 39 of 41

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

GnomAD2 exomes

AF:

0.0301

AC:

7568

AN:

251372

AF XY:

0.0305

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 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

African (AFR)

AF:

0.00562

AC:

188

AN:

33480

American (AMR)

AF:

0.0152

AC:

681

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0113

AC:

295

AN:

26136

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39700

South Asian (SAS)

AF:

0.0117

AC:

1005

AN:

86256

European-Finnish (FIN)

AF:

0.0726

AC:

3878

AN:

53412

Middle Eastern (MID)

AF:

0.00520

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0434

AC:

48284

AN:

1111996

Other (OTH)

AF:

0.0306

AC:

1845

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

3104

6208

9311

12415

15519

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1746

3492

5238

6984

8730

<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:

0.0297

AC:

4523

AN:

152206

Hom.:

104

Cov.:

AF XY:

0.0307

AC XY:

2288

AN XY:

74414

show subpopulations

African (AFR)

AF:

0.00809

AC:

336

AN:

41544

American (AMR)

AF:

0.0178

AC:

272

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.0133

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.0124

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.0722

AC:

765

AN:

10598

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0435

AC:

2958

AN:

67996

Other (OTH)

AF:

0.0251

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

225

450

675

900

1125

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

162

216

270

<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:

0.0305

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

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Hereditary spastic paraplegia 15 (2)

not specified (2)

Hereditary spastic paraplegia (1)

Spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.41

CADD

Benign

(source)

DANN

Uncertain

1.0

Eigen

Benign

0.16

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Benign

0.72

LIST_S2

Benign

0.83

MetaRNN

Benign

0.0029

MetaSVM

Benign

-1.1

PhyloP100

2.5

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.77

REVEL

Benign

0.056

Sift

Benign

0.14

Sift4G

Uncertain

0.0080

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

Mutation Taster

=93/7

polymorphism (auto)

(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