rs146968463

Variant names:

• chr14-67775076-C-T
• rs146968463
• NM_015346.4:c.5260G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_015346.4(ZFYVE26):​c.5260G>A​(p.Ala1754Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000749 in 1,612,254 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00042 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00078 (1 hom.)
• Consequence: ZFYVE26 NM_015346.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:11 B:3
• Conservation: PhyloP100: 0.774
• Publications: 2 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.019519866).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015346.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZFYVE26	NM_015346.4	MANE Select	c.5260G>A	p.Ala1754Thr	missense	Exon 27 of 42	NP_056161.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZFYVE26	ENST00000347230.9	TSL:1 MANE Select	c.5260G>A	p.Ala1754Thr	missense	Exon 27 of 42	ENSP00000251119.5
	ZFYVE26	ENST00000555452.1	TSL:1	c.5260G>A	p.Ala1754Thr	missense	Exon 27 of 35	ENSP00000450603.1
	ZFYVE26	ENST00000554523.5	TSL:1	n.5397G>A		non_coding_transcript_exon	Exon 27 of 41

Frequencies

GnomAD3 genomes AF: 0.000421 AC: 64 AN: 152114 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000794

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000375 AC: 93 AN: 248244 AF XY: 0.000403

Gnomad AFR exome AF: 0.000561

Gnomad AMR exome AF: 0.0000293

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000929

Gnomad NFE exome AF: 0.000720

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000783 AC: 1143 AN: 1460022 Hom.: 1 Cov.: 31 AF XY: 0.000788 AC XY: 572 AN XY: 726128

African (AFR) AF: 0.000269 AC: 9 AN: 33408

American (AMR) AF: 0.00 AC: 0 AN: 44400

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26070

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 85590

European-Finnish (FIN) AF: 0.0000937 AC: 5 AN: 53360

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5758

European-Non Finnish (NFE) AF: 0.000994 AC: 1105 AN: 1111410

Other (OTH) AF: 0.000381 AC: 23 AN: 60336

GnomAD4 genome AF: 0.000420 AC: 64 AN: 152232 Hom.: 0 Cov.: 32 AF XY: 0.000430 AC XY: 32 AN XY: 74428

African (AFR) AF: 0.000193 AC: 8 AN: 41540

American (AMR) AF: 0.00 AC: 0 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.000189 AC: 2 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000794 AC: 54 AN: 68006

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000629 Hom.: 0

Bravo AF: 0.000416

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00116 AC: 10

ExAC AF: 0.000231 AC: 28

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	3	not provided (5)
-	4	-	Hereditary spastic paraplegia 15 (4)
-	2	-	not specified (2)
-	1	-	Hereditary spastic paraplegia (1)
-	1	-	Inborn genetic diseases (1)
-	1	-	Spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0054	T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.52	D
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.020	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.77
PrimateAI	Benign	0.34	T
PROVEAN	Benign	0.33	N
REVEL	Benign	0.018
Sift	Benign	0.55	T
Sift4G	Benign	0.28	T
Polyphen		0.10	B
Vest4		0.18
MVP		0.072
MPC		0.16
ClinPred		0.025	T
GERP RS		4.9
gMVP		0.24
Mutation Taster		=93/7	polymorphism

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

Other links and lift over

dbSNP: rs146968463; hg19: chr14-68241793; COSMIC: COSV61332273; COSMIC: COSV61332273;