10-97738477-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_001385875.1(ZFYVE27):c.-1G>A variant causes a splice region, 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.575 in 1,613,308 control chromosomes in the GnomAD database, including 272,882 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.52 (21508 hom., cov: 32)
  • Exomes 𝑓: 0.58 (251374 hom.)
• Consequence: ZFYVE27 NM_001385875.1 splice_region, 5_prime_UTR
• Scores: Splicing: ADA: 0.0001649
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.749

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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 10-97738477-G-A is Benign according to our data. Variant chr10-97738477-G-A is described in ClinVar as [Benign]. Clinvar id is 301827.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-97738477-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.605 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZFYVE27	NM_001385875.1	c.-1G>A		splice_region_variant, 5_prime_UTR_variant	2/13	ENST00000684270.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZFYVE27	ENST00000684270.1	c.-1G>A		splice_region_variant, 5_prime_UTR_variant	2/13		NM_001385875.1	A1

Frequencies

GnomAD3 genomes AF: 0.516 AC: 78479 AN: 151966 Hom.: 21506 Cov.: 32

Gnomad AFR AF: 0.346

Gnomad AMI AF: 0.648

Gnomad AMR AF: 0.486

Gnomad ASJ AF: 0.616

Gnomad EAS AF: 0.326

Gnomad SAS AF: 0.486

Gnomad FIN AF: 0.681

Gnomad MID AF: 0.611

Gnomad NFE AF: 0.610

Gnomad OTH AF: 0.529

GnomAD3 exomes AF: 0.531 AC: 133326 AN: 251274 Hom.: 37097 AF XY: 0.536 AC XY: 72878 AN XY: 135860

Gnomad AFR exome AF: 0.339

Gnomad AMR exome AF: 0.423

Gnomad ASJ exome AF: 0.610

Gnomad EAS exome AF: 0.308

Gnomad SAS exome AF: 0.475

Gnomad FIN exome AF: 0.671

Gnomad NFE exome AF: 0.606

Gnomad OTH exome AF: 0.569

GnomAD4 exome AF: 0.581 AC: 848530 AN: 1461224 Hom.: 251374 Cov.: 47 AF XY: 0.579 AC XY: 420867 AN XY: 726964

Gnomad4 AFR exome AF: 0.337

Gnomad4 AMR exome AF: 0.429

Gnomad4 ASJ exome AF: 0.614

Gnomad4 EAS exome AF: 0.325

Gnomad4 SAS exome AF: 0.471

Gnomad4 FIN exome AF: 0.669

Gnomad4 NFE exome AF: 0.608

Gnomad4 OTH exome AF: 0.552

GnomAD4 genome AF: 0.516 AC: 78482 AN: 152084 Hom.: 21508 Cov.: 32 AF XY: 0.517 AC XY: 38472 AN XY: 74348

Gnomad4 AFR AF: 0.345

Gnomad4 AMR AF: 0.485

Gnomad4 ASJ AF: 0.616

Gnomad4 EAS AF: 0.326

Gnomad4 SAS AF: 0.487

Gnomad4 FIN AF: 0.681

Gnomad4 NFE AF: 0.610

Gnomad4 OTH AF: 0.529

Alfa AF: 0.587 Hom.: 56350

Bravo AF: 0.492

Asia WGS AF: 0.425 AC: 1479 AN: 3478

EpiCase AF: 0.609

EpiControl AF: 0.610

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary spastic paraplegia 33 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -

Spastic paraplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Nov 22, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
Cadd	Benign	16
Dann	Benign	0.83

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00016
dbscSNV1_RF	Benign	0.0020
SpliceAI score (max)		0.10		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: rs3818876; hg19: chr10-99498234; COSMIC: COSV61746431;