rs12891047

Variant names:

• chr14-67776358-C-A
• rs12891047
• NM_015346.4:c.4975-252G>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_015346.4(ZFYVE26):​c.4975-252G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.622 in 152,014 control chromosomes in the GnomAD database, including 30,201 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.62 (30201 hom., cov: 32)
• Consequence: ZFYVE26 NM_015346.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.488
• Publications: 11 publications found

Genes affected

ZFYVE26 (HGNC:20761): (zinc finger FYVE-type containing 26) This gene encodes a protein which contains a FYVE zinc finger binding domain. The presence of this domain is thought to target these proteins to membrane lipids through interaction with phospholipids in the membrane. Mutations in this gene are associated with autosomal recessive spastic paraplegia-15. [provided by RefSeq, Oct 2008]

ZFYVE26 Gene-Disease associations (from GenCC):

• hereditary spastic paraplegia 15

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Myriad Women’s Health, G2P

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 14-67776358-C-A is Benign according to our data. Variant chr14-67776358-C-A is described in ClinVar as Benign. ClinVar VariationId is 669979.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.902 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZFYVE26	NM_015346.4	c.4975-252G>T		intron_variant	Intron 25 of 41	ENST00000347230.9	NP_056161.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZFYVE26	ENST00000347230.9	c.4975-252G>T		intron_variant	Intron 25 of 41	1	NM_015346.4	ENSP00000251119.5

Frequencies

GnomAD3 genomes AF: 0.622 AC: 94505 AN: 151896 Hom.: 30176 Cov.: 32

Gnomad AFR AF: 0.506

Gnomad AMI AF: 0.651

Gnomad AMR AF: 0.721

Gnomad ASJ AF: 0.553

Gnomad EAS AF: 0.924

Gnomad SAS AF: 0.753

Gnomad FIN AF: 0.712

Gnomad MID AF: 0.506

Gnomad NFE AF: 0.628

Gnomad OTH AF: 0.617

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.622 AC: 94568 AN: 152014 Hom.: 30201 Cov.: 32 AF XY: 0.632 AC XY: 47017 AN XY: 74338

African (AFR) AF: 0.506 AC: 20939 AN: 41416

American (AMR) AF: 0.721 AC: 11030 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.553 AC: 1920 AN: 3470

East Asian (EAS) AF: 0.924 AC: 4781 AN: 5174

South Asian (SAS) AF: 0.752 AC: 3621 AN: 4818

European-Finnish (FIN) AF: 0.712 AC: 7535 AN: 10576

Middle Eastern (MID) AF: 0.486 AC: 143 AN: 294

European-Non Finnish (NFE) AF: 0.628 AC: 42692 AN: 67952

Other (OTH) AF: 0.622 AC: 1313 AN: 2110

Alfa AF: 0.627 Hom.: 107205

Bravo AF: 0.616

Asia WGS AF: 0.808 AC: 2811 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.35
DANN	Benign	0.55
PhyloP100		-0.49
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs12891047; hg19: chr14-68243075;