10-97743140-G-A

Variant names:

• chr10-97743140-G-A
• rs17108378
• NM_001385875.1:c.244G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001385875.1(ZFYVE27):​c.244G>A​(p.Val82Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0307 in 1,614,168 control chromosomes in the GnomAD database, including 900 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.029 (73 hom., cov: 32)
  • Exomes 𝑓: 0.031 (827 hom.)
• Consequence: ZFYVE27 NM_001385875.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.14
• Publications: 19 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: Labcorp Genetics (formerly Invitae), ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0020341873).
• BP6: Variant 10-97743140-G-A is Benign according to our data. Variant chr10-97743140-G-A is described in ClinVar as Benign. ClinVar VariationId is 130785.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0544 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZFYVE27	NM_001385875.1	c.244G>A	p.Val82Ile	missense_variant	Exon 3 of 13	ENST00000684270.1	NP_001372804.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZFYVE27	ENST00000684270.1	c.244G>A	p.Val82Ile	missense_variant	Exon 3 of 13		NM_001385875.1	ENSP00000506975.1

Frequencies

GnomAD3 genomes AF: 0.0295 AC: 4483 AN: 152192 Hom.: 72 Cov.: 32

Gnomad AFR AF: 0.0295

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0287

Gnomad ASJ AF: 0.0476

Gnomad EAS AF: 0.0359

Gnomad SAS AF: 0.0522

Gnomad FIN AF: 0.0153

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0292

Gnomad OTH AF: 0.0302

GnomAD2 exomes AF: 0.0321 AC: 8063 AN: 251492 AF XY: 0.0340

Gnomad AFR exome AF: 0.0305

Gnomad AMR exome AF: 0.0166

Gnomad ASJ exome AF: 0.0434

Gnomad EAS exome AF: 0.0379

Gnomad FIN exome AF: 0.0188

Gnomad NFE exome AF: 0.0314

Gnomad OTH exome AF: 0.0309

GnomAD4 exome AF: 0.0308 AC: 45083 AN: 1461858 Hom.: 827 Cov.: 32 AF XY: 0.0318 AC XY: 23162 AN XY: 727230

African (AFR) AF: 0.0295 AC: 987 AN: 33478

American (AMR) AF: 0.0177 AC: 790 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0430 AC: 1124 AN: 26134

East Asian (EAS) AF: 0.0391 AC: 1551 AN: 39700

South Asian (SAS) AF: 0.0558 AC: 4810 AN: 86254

European-Finnish (FIN) AF: 0.0195 AC: 1044 AN: 53420

Middle Eastern (MID) AF: 0.0324 AC: 187 AN: 5768

European-Non Finnish (NFE) AF: 0.0294 AC: 32650 AN: 1111984

Other (OTH) AF: 0.0321 AC: 1940 AN: 60396

GnomAD4 genome AF: 0.0295 AC: 4486 AN: 152310 Hom.: 73 Cov.: 32 AF XY: 0.0294 AC XY: 2189 AN XY: 74486

African (AFR) AF: 0.0295 AC: 1224 AN: 41562

American (AMR) AF: 0.0286 AC: 438 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0476 AC: 165 AN: 3470

East Asian (EAS) AF: 0.0358 AC: 186 AN: 5192

South Asian (SAS) AF: 0.0527 AC: 254 AN: 4822

European-Finnish (FIN) AF: 0.0153 AC: 162 AN: 10616

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0292 AC: 1984 AN: 68028

Other (OTH) AF: 0.0299 AC: 63 AN: 2110

Alfa AF: 0.0306 Hom.: 330

Bravo AF: 0.0301

TwinsUK AF: 0.0283 AC: 105

ALSPAC AF: 0.0285 AC: 110

ESP6500AA AF: 0.0327 AC: 144

ESP6500EA AF: 0.0315 AC: 271

ExAC AF: 0.0334 AC: 4055

Asia WGS AF: 0.0370 AC: 128 AN: 3478

EpiCase AF: 0.0302

EpiControl AF: 0.0308

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary spastic paraplegia 33 Benign:2

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Spastic paraplegia Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.046
DANN	Benign	0.78
DEOGEN2	Benign	0.0040	T;.;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.069	N
LIST_S2	Benign	0.51	T;T;T
MetaRNN	Benign	0.0020	T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-1.5	N;N;N
PhyloP100		-1.1
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.060	N;.;N
REVEL	Benign	0.018
Sift	Benign	1.0	T;.;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0	B;B;B
Vest4		0.064
ClinPred		0.0029	T
GERP RS		-7.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.018
gMVP		0.085
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs17108378; hg19: chr10-99502897;