rs148925506

Positions:

• chr14-67781500-C-A
• chr14-67781500-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_015346.4(ZFYVE26):​c.4402G>T​(p.Val1468Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,850 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1468M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ZFYVE26 NM_015346.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.01

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26643205).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZFYVE26	NM_015346.4	c.4402G>T	p.Val1468Leu	missense_variant	22/42	ENST00000347230.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZFYVE26	ENST00000347230.9	c.4402G>T	p.Val1468Leu	missense_variant	22/42	1	NM_015346.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250722 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135570

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461850 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727222

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.027	.;T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.83	.;T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.27	T;T
MetaSVM	Benign	-0.95	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.1	N;N
REVEL	Benign	0.089
Sift	Benign	0.084	T;T
Sift4G	Uncertain	0.015	D;D
Polyphen		0.99	.;D
Vest4		0.42
MutPred		0.30		Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);
MVP		0.36
MPC		0.24
ClinPred		0.72	D
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
gMVP		0.23

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs148925506; hg19: chr14-68248217; COSMIC: COSV61324234; COSMIC: COSV61324234;