10-97738603-C-T

Position:

• chr10-97738603-C-T

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_001385875.1(ZFYVE27):​c.126C>T​(p.Leu42=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00712 in 1,613,914 control chromosomes in the GnomAD database, including 53 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0051 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0073 (49 hom.)
• Consequence: ZFYVE27 NM_001385875.1 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.392

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 10-97738603-C-T is Benign according to our data. Variant chr10-97738603-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 238205.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-97738603-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.392 with no splicing effect.
• BS2: High AC in GnomAd4 at 768 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZFYVE27	NM_001385875.1	c.126C>T	p.Leu42=	synonymous_variant	2/13	ENST00000684270.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZFYVE27	ENST00000684270.1	c.126C>T	p.Leu42=	synonymous_variant	2/13		NM_001385875.1	A1

Frequencies

GnomAD3 genomes AF: 0.00507 AC: 770 AN: 151912 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00116

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00688

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.00123

Gnomad MID AF: 0.0132

Gnomad NFE AF: 0.00840

Gnomad OTH AF: 0.00482

GnomAD3 exomes AF: 0.00489 AC: 1229 AN: 251496 Hom.: 6 AF XY: 0.00532 AC XY: 723 AN XY: 135922

Gnomad AFR exome AF: 0.00160

Gnomad AMR exome AF: 0.00515

Gnomad ASJ exome AF: 0.000595

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00408

Gnomad FIN exome AF: 0.00176

Gnomad NFE exome AF: 0.00708

Gnomad OTH exome AF: 0.00831

GnomAD4 exome AF: 0.00734 AC: 10723 AN: 1461880 Hom.: 49 Cov.: 33 AF XY: 0.00724 AC XY: 5264 AN XY: 727242

Gnomad4 AFR exome AF: 0.00105

Gnomad4 AMR exome AF: 0.00521

Gnomad4 ASJ exome AF: 0.000727

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00435

Gnomad4 FIN exome AF: 0.00176

Gnomad4 NFE exome AF: 0.00853

Gnomad4 OTH exome AF: 0.00727

GnomAD4 genome AF: 0.00505 AC: 768 AN: 152034 Hom.: 4 Cov.: 32 AF XY: 0.00461 AC XY: 343 AN XY: 74350

Gnomad4 AFR AF: 0.00116

Gnomad4 AMR AF: 0.00687

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00248

Gnomad4 FIN AF: 0.00123

Gnomad4 NFE AF: 0.00839

Gnomad4 OTH AF: 0.00429

Alfa AF: 0.00658 Hom.: 2

Bravo AF: 0.00501

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00921

EpiControl AF: 0.00889

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

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

Jan 24, 2024

- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jun 25, 2015

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Dec 01, 2022

ZFYVE27: BP4, BP7, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	6.7
DANN	Benign	0.88

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: rs17419023; hg19: chr10-99498360; COSMIC: COSV100519453;