Genetic Variant NM_001385875.1:c.424C>G (chr10-97744884-C-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001385875.1(ZFYVE27):c.424C>G(p.Arg142Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000207 in 1,449,430 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R142C) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

ZFYVE27
NM_001385875.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.90

Publications

3 publications found

Variant links:

Genes affected

ZFYVE27 (HGNC:26559): (zinc finger FYVE-type containing 27) This gene encodes a protein with several transmembrane domains, a Rab11-binding domain and a lipid-binding FYVE finger domain. The encoded protein appears to promote neurite formation. A mutation in this gene has been reported to be associated with hereditary spastic paraplegia, however the pathogenicity of the mutation, which may simply represent a polymorphism, is unclear. [provided by RefSeq, Mar 2010]

ZFYVE27 Gene-Disease associations (from GenCC):

hereditary spastic paraplegia 33
Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)

ZFYVE27 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001385875.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ZFYVE27	NM_001385875.1	MANE Select	c.424C>G	p.Arg142Gly	missense	Exon 4 of 13	NP_001372804.1	Q5T4F4-1
ZFYVE27	NM_001385876.1		c.463C>G	p.Arg155Gly	missense	Exon 5 of 13	NP_001372805.1
ZFYVE27	NM_001002261.4		c.424C>G	p.Arg142Gly	missense	Exon 4 of 13	NP_001002261.1	Q5T4F4-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ZFYVE27	ENST00000684270.1	MANE Select	c.424C>G	p.Arg142Gly	missense	Exon 4 of 13	ENSP00000506975.1	Q5T4F4-1
ZFYVE27	ENST00000393677.8	TSL:1	c.424C>G	p.Arg142Gly	missense	Exon 4 of 13	ENSP00000377282.3	Q5T4F4-1
ZFYVE27	ENST00000423811.3	TSL:5	c.424C>G	p.Arg142Gly	missense	Exon 4 of 13	ENSP00000409594.2	Q5T4F4-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000207

AC:

AN:

1449430

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

719984

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33324

American (AMR)

AF:

0.00

AC:

AN:

43306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25884

East Asian (EAS)

AF:

0.00

AC:

AN:

39480

South Asian (SAS)

AF:

0.00

AC:

AN:

84902

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51772

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5622

European-Non Finnish (NFE)

AF:

0.00000271

AC:

AN:

1105288

Other (OTH)

AF:

0.00

AC:

AN:

59852

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.442

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

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.33

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.15

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.026

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.43

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.89

M_CAP

Benign

0.069

MetaRNN

Uncertain

0.70

MetaSVM

Benign

-0.58

MutationAssessor

Uncertain

2.0

PhyloP100

2.9

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-1.8

REVEL

Benign

0.29

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0070

Polyphen

1.0

Vest4

0.81

MutPred

0.37

Loss of helix (P = 0.028)

MVP

0.51

ClinPred

0.83

GERP RS

5.7

Varity_R

0.37

gMVP

0.62

Mutation Taster

=60/40

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over