Genetic Variant NM_015346.4:c.3062G>A (chr14-67786191-C-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_015346.4(ZFYVE26):c.3062G>A(p.Arg1021Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000412 in 1,603,088 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. R1021R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000028 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000042 ( 0 hom. )

Consequence

ZFYVE26
NM_015346.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 1.01

Publications

1 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), Orphanet, Myriad Women’s Health, G2P

ZFYVE26 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.037067115).

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.3062G>A	p.Arg1021Gln	missense	Exon 17 of 42	NP_056161.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ZFYVE26	ENST00000347230.9	TSL:1 MANE Select	c.3062G>A	p.Arg1021Gln	missense	Exon 17 of 42	ENSP00000251119.5
ZFYVE26	ENST00000555452.1	TSL:1	c.3062G>A	p.Arg1021Gln	missense	Exon 17 of 35	ENSP00000450603.1
ZFYVE26	ENST00000554523.5	TSL:1	n.3199G>A		non_coding_transcript_exon	Exon 17 of 41

Frequencies

GnomAD3 genomes

AF:

0.0000278

AC:

AN:

144082

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000643

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000149

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000115

AC:

AN:

251366

AF XY:

0.000169

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000425

AC:

AN:

1458898

Hom.:

Cov.:

AF XY:

0.0000661

AC XY:

AN XY:

725788

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33404

American (AMR)

AF:

0.00

AC:

AN:

44612

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26046

East Asian (EAS)

AF:

0.0000255

AC:

AN:

39278

South Asian (SAS)

AF:

0.000673

AC:

AN:

86180

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53190

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

9.01e-7

AC:

AN:

1110262

Other (OTH)

AF:

0.0000166

AC:

AN:

60172

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

AF:

0.0000277

AC:

AN:

144190

Hom.:

Cov.:

AF XY:

0.0000289

AC XY:

AN XY:

69102

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

39220

American (AMR)

AF:

0.00

AC:

AN:

13182

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3454

East Asian (EAS)

AF:

0.00

AC:

AN:

4754

South Asian (SAS)

AF:

0.000644

AC:

AN:

4662

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8532

Middle Eastern (MID)

AF:

0.00

AC:

AN:

268

European-Non Finnish (NFE)

AF:

0.0000149

AC:

AN:

67226

Other (OTH)

AF:

0.00

AC:

AN:

1988

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.613

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.000148

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

Spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.53

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.018

Eigen

Benign

-0.13

Eigen_PC

Benign

0.010

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.79

M_CAP

Benign

0.010

MetaRNN

Benign

0.037

MetaSVM

Benign

-1.1

PhyloP100

1.0

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.91

REVEL

Benign

0.036

Sift

Benign

0.047

Sift4G

Uncertain

0.010

Polyphen

0.14

Vest4

0.28

MutPred

0.40

Loss of MoRF binding (P = 0.0451)

MVP

0.32

MPC

0.19

ClinPred

0.11

GERP RS

4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

gMVP

0.25

Mutation Taster

=95/5

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