rs138664542

Variant names:

• chr14-67813993-C-G
• rs138664542
• NM_015346.4:c.266G>C

Your query was ambiguous. Multiple possible variants found:

• chr14-67813993-C-G
• chr14-67813993-C-T

Variant summary

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

The NM_015346.4(ZFYVE26):​c.266G>C​(p.Arg89Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000508 in 1,613,236 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R89Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000052 (0 hom.)
• Consequence: ZFYVE26 NM_015346.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.367
• 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), G2P, Orphanet, Myriad Women’s Health

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.031804144).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZFYVE26	NM_015346.4	MANE Select	c.266G>C	p.Arg89Pro	missense	Exon 3 of 42	NP_056161.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZFYVE26	ENST00000347230.9	TSL:1 MANE Select	c.266G>C	p.Arg89Pro	missense	Exon 3 of 42	ENSP00000251119.5	Q68DK2-1
	ZFYVE26	ENST00000555452.1	TSL:1	c.266G>C	p.Arg89Pro	missense	Exon 3 of 35	ENSP00000450603.1	G3V2D8
	ZFYVE26	ENST00000554523.5	TSL:1	n.403G>C		non_coding_transcript_exon	Exon 3 of 41

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152166 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000558 AC: 14 AN: 251012 AF XY: 0.0000590

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000498

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000704

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000520 AC: 76 AN: 1460952 Hom.: 0 Cov.: 30 AF XY: 0.0000592 AC XY: 43 AN XY: 726808

African (AFR) AF: 0.0000598 AC: 2 AN: 33464

American (AMR) AF: 0.0000224 AC: 1 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.000383 AC: 10 AN: 26096

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86186

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53386

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.0000432 AC: 48 AN: 1111296

Other (OTH) AF: 0.000133 AC: 8 AN: 60370

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152284 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74456

African (AFR) AF: 0.00 AC: 0 AN: 41542

American (AMR) AF: 0.00 AC: 0 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000174 Hom.: 0

Bravo AF: 0.0000378

ExAC AF: 0.0000824 AC: 10

EpiCase AF: 0.000218

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Hereditary spastic paraplegia 15 (1)
-	1	-	Spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	0.82
DANN	Benign	0.76
DEOGEN2	Benign	0.014	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.080	N
LIST_S2	Benign	0.21	T
M_CAP	Benign	0.0076	T
MetaRNN	Benign	0.032	T
MetaSVM	Benign	-0.99	T
PhyloP100		-0.37
PrimateAI	Benign	0.19	T
PROVEAN	Benign	-0.090	N
REVEL	Benign	0.044
Sift	Benign	0.37	T
Sift4G	Benign	0.29	T
Polyphen		0.0	B
Vest4		0.24
MutPred		0.46		Loss of MoRF binding (P = 0.0011)
MVP		0.12
MPC		0.24
ClinPred		0.024	T
GERP RS		-11
gMVP		0.37
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: rs138664542; hg19: chr14-68280710;