14-67748497-C-T

Variant names:

• chr14-67748497-C-T
• NM_015346.4:c.7559G>A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_015346.4(ZFYVE26):​c.7559G>A​(p.Cys2520Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,296 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ZFYVE26 NM_015346.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.47

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.861

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZFYVE26	NM_015346.4	c.7559G>A	p.Cys2520Tyr	missense_variant	Exon 42 of 42	ENST00000347230.9	NP_056161.2
ZFYVE26	XM_047431174.1	c.5234G>A	p.Cys1745Tyr	missense_variant	Exon 31 of 31		XP_047287130.1
ZFYVE26	XM_047431175.1	c.5141G>A	p.Cys1714Tyr	missense_variant	Exon 31 of 31		XP_047287131.1
ZFYVE26	XM_047431173.1	c.7416+2555G>A		intron_variant	Intron 41 of 41		XP_047287129.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZFYVE26	ENST00000347230.9	c.7559G>A	p.Cys2520Tyr	missense_variant	Exon 42 of 42	1	NM_015346.4	ENSP00000251119.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461296 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726940

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: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	26
DANN	Uncertain	1.0
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	1.0	D
M_CAP	Uncertain	0.089	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Benign	-0.49	T
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-8.2	D
REVEL	Uncertain	0.53
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.85
MutPred		0.67		Gain of phosphorylation at C2520 (P = 0.0229);
MVP		0.66
MPC		0.90
ClinPred		1.0	D
GERP RS		5.7
gMVP		0.76

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-68215214;