chr10-97744884-C-G

Variant names:

• chr10-97744884-C-G
• rs145746084
• NM_001385875.1:c.424C>G

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.90
• Publications: 3 publications found

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)

ACMG classification

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

Sel.	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

Sel.	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.: 34

GnomAD4 exome AF: 0.00000207 AC: 3 AN: 1449430 Hom.: 0 Cov.: 38 AF XY: 0.00000139 AC XY: 1 AN XY: 719984

African (AFR) AF: 0.00 AC: 0 AN: 33324

American (AMR) AF: 0.00 AC: 0 AN: 43306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25884

East Asian (EAS) AF: 0.00 AC: 0 AN: 39480

South Asian (SAS) AF: 0.00 AC: 0 AN: 84902

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51772

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5622

European-Non Finnish (NFE) AF: 0.00000271 AC: 3 AN: 1105288

Other (OTH) AF: 0.00 AC: 0 AN: 59852

GnomAD4 genome Cov.: 34

Alfa AF: 0.00 Hom.: 1

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	D
BayesDel_noAF	Pathogenic	0.15
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.026	T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.069	D
MetaRNN	Uncertain	0.70	D
MetaSVM	Benign	-0.58	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		2.9
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.29
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0070	D
Polyphen		1.0	D
Vest4		0.81
MutPred		0.37		Loss of helix (P = 0.028)
MVP		0.51
ClinPred		0.83	D
GERP RS		5.7
Varity_R		0.37
gMVP		0.62
Mutation Taster		=60/40	polymorphism

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

Other links and lift over

dbSNP: rs145746084; hg19: chr10-99504641;