rs75060573

Positions:

• chr10-97744838-G-A
• chr10-97744838-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001385875.1(ZFYVE27):​c.378G>A​(p.Lys126=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.029 in 1,613,534 control chromosomes in the GnomAD database, including 822 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.020 (43 hom., cov: 33)
  • Exomes 𝑓: 0.030 (779 hom.)
• Consequence: ZFYVE27 NM_001385875.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.78

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 10-97744838-G-A is Benign according to our data. Variant chr10-97744838-G-A is described in ClinVar as [Benign]. Clinvar id is 130786.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-97744838-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=1.78 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0202 (3071/152392) while in subpopulation SAS AF= 0.0435 (210/4832). AF 95% confidence interval is 0.0386. There are 43 homozygotes in gnomad4. There are 1422 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 3071 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZFYVE27	NM_001385875.1	c.378G>A	p.Lys126=	synonymous_variant	4/13	ENST00000684270.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZFYVE27	ENST00000684270.1	c.378G>A	p.Lys126=	synonymous_variant	4/13		NM_001385875.1	A1

Frequencies

GnomAD3 genomes AF: 0.0202 AC: 3073 AN: 152274 Hom.: 42 Cov.: 33

Gnomad AFR AF: 0.00571

Gnomad AMI AF: 0.0351

Gnomad AMR AF: 0.0118

Gnomad ASJ AF: 0.0251

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0434

Gnomad FIN AF: 0.0108

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0317

Gnomad OTH AF: 0.0234

GnomAD3 exomes AF: 0.0234 AC: 5844 AN: 250064 Hom.: 115 AF XY: 0.0256 AC XY: 3454 AN XY: 135154

Gnomad AFR exome AF: 0.00422

Gnomad AMR exome AF: 0.00849

Gnomad ASJ exome AF: 0.0285

Gnomad EAS exome AF: 0.000218

Gnomad SAS exome AF: 0.0466

Gnomad FIN exome AF: 0.0115

Gnomad NFE exome AF: 0.0298

Gnomad OTH exome AF: 0.0262

GnomAD4 exome AF: 0.0299 AC: 43752 AN: 1461142 Hom.: 779 Cov.: 30 AF XY: 0.0305 AC XY: 22150 AN XY: 726780

Gnomad4 AFR exome AF: 0.00373

Gnomad4 AMR exome AF: 0.00949

Gnomad4 ASJ exome AF: 0.0271

Gnomad4 EAS exome AF: 0.000202

Gnomad4 SAS exome AF: 0.0473

Gnomad4 FIN exome AF: 0.0139

Gnomad4 NFE exome AF: 0.0322

Gnomad4 OTH exome AF: 0.0284

GnomAD4 genome AF: 0.0202 AC: 3071 AN: 152392 Hom.: 43 Cov.: 33 AF XY: 0.0191 AC XY: 1422 AN XY: 74520

Gnomad4 AFR AF: 0.00567

Gnomad4 AMR AF: 0.0118

Gnomad4 ASJ AF: 0.0251

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0435

Gnomad4 FIN AF: 0.0108

Gnomad4 NFE AF: 0.0317

Gnomad4 OTH AF: 0.0227

Alfa AF: 0.0245 Hom.: 38

Bravo AF: 0.0192

Asia WGS AF: 0.0180 AC: 65 AN: 3478

EpiCase AF: 0.0300

EpiControl AF: 0.0291

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 02, 2016	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	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. -

Hereditary spastic paraplegia 33 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -

Spastic paraplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	7.9
DANN	Benign	0.51

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

LitVar

Other links and lift over

dbSNP: rs75060573; hg19: chr10-99504595;