chr14-67783430-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_015346.4(ZFYVE26):c.3722G>A(p.Arg1241Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00325 in 1,614,066 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. R1241R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0026 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0033 ( 17 hom. )

Consequence

ZFYVE26
NM_015346.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:10

Conservation

PhyloP100: -0.433

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004694402).

BP6

Variant 14-67783430-C-T is Benign according to our data. Variant chr14-67783430-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 288592.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00265 (403/152218) while in subpopulation AMR AF = 0.00445 (68/15298). AF 95% confidence interval is 0.0036. There are 1 homozygotes in GnomAd4. There are 193 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 17 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.3722G>A	p.Arg1241Gln	missense	Exon 21 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.3722G>A	p.Arg1241Gln	missense	Exon 21 of 42	ENSP00000251119.5	Q68DK2-1
ZFYVE26	ENST00000555452.1	TSL:1	c.3722G>A	p.Arg1241Gln	missense	Exon 21 of 35	ENSP00000450603.1	G3V2D8
ZFYVE26	ENST00000554523.5	TSL:1	n.3859G>A		non_coding_transcript_exon	Exon 21 of 41

Frequencies

GnomAD3 genomes

AF:

0.00265

AC:

403

AN:

152102

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000411

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00445

Gnomad ASJ

AF:

0.00894

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00332

Gnomad FIN

AF:

0.00113

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00354

Gnomad OTH

AF:

0.00669

GnomAD2 exomes

AF:

0.00309

AC:

776

AN:

251098

AF XY:

0.00335

show subpopulations

Gnomad AFR exome

AF:

0.000492

Gnomad AMR exome

AF:

0.00315

Gnomad ASJ exome

AF:

0.00914

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00176

Gnomad NFE exome

AF:

0.00360

Gnomad OTH exome

AF:

0.00637

GnomAD4 exome

AF:

0.00331

AC:

4844

AN:

1461848

Hom.:

Cov.:

AF XY:

0.00346

AC XY:

2518

AN XY:

727220

show subpopulations

African (AFR)

AF:

0.000568

AC:

AN:

33480

American (AMR)

AF:

0.00309

AC:

138

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0103

AC:

269

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.00344

AC:

297

AN:

86254

European-Finnish (FIN)

AF:

0.00144

AC:

AN:

53384

Middle Eastern (MID)

AF:

0.0258

AC:

149

AN:

5768

European-Non Finnish (NFE)

AF:

0.00323

AC:

3595

AN:

1112006

Other (OTH)

AF:

0.00495

AC:

299

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

324

648

971

1295

1619

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

126

252

378

504

630

<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:

0.00265

AC:

403

AN:

152218

Hom.:

Cov.:

AF XY:

0.00259

AC XY:

193

AN XY:

74436

show subpopulations

African (AFR)

AF:

0.000409

AC:

AN:

41518

American (AMR)

AF:

0.00445

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00894

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00332

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00113

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00354

AC:

241

AN:

68008

Other (OTH)

AF:

0.00662

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

106

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:

0.00380

Hom.:

Bravo

AF:

0.00298

TwinsUK

AF:

0.00189

AC:

ALSPAC

AF:

0.00311

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00372

AC:

ExAC

AF:

0.00283

AC:

344

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.00534

EpiControl

AF:

0.00616

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (6)

Hereditary spastic paraplegia 15 (2)

Hereditary spastic paraplegia (1)

not specified (1)

Spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.67

CADD

Benign

2.4

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.012

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.038

LIST_S2

Benign

0.66

M_CAP

Benign

0.0040

MetaRNN

Benign

0.0047

MetaSVM

Benign

-1.0

PhyloP100

-0.43

PrimateAI

Benign

0.20

PROVEAN

Benign

-0.90

REVEL

Benign

0.11

Sift

Benign

0.13

Sift4G

Benign

0.096

Polyphen

0.99

Vest4

0.054

MVP

0.040

MPC

0.19

ClinPred

0.018

GERP RS

-11

gMVP

0.10

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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