rs17192170

Variant names:

• chr14-67790635-T-A
• rs17192170
• NM_015346.4:c.2692A>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_015346.4(ZFYVE26):​c.2692A>T​(p.Thr898Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.115 in 1,614,134 control chromosomes in the GnomAD database, including 11,951 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T898T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.090 (878 hom., cov: 33)
  • Exomes 𝑓: 0.12 (11073 hom.)
• Consequence: ZFYVE26 NM_015346.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.26
• Publications: 13 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0013203025).
• BP6: Variant 14-67790635-T-A is Benign according to our data. Variant chr14-67790635-T-A is described in ClinVar as Benign. ClinVar VariationId is 313909.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.125 is higher than 0.05.

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.2692A>T	p.Thr898Ser	missense	Exon 15 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.2692A>T	p.Thr898Ser	missense	Exon 15 of 42	ENSP00000251119.5
	ZFYVE26	ENST00000555452.1	TSL:1	c.2692A>T	p.Thr898Ser	missense	Exon 15 of 35	ENSP00000450603.1
	ZFYVE26	ENST00000554523.5	TSL:1	n.2829A>T		non_coding_transcript_exon	Exon 15 of 41

Frequencies

GnomAD3 genomes AF: 0.0896 AC: 13642 AN: 152182 Hom.: 879 Cov.: 33

Gnomad AFR AF: 0.0236

Gnomad AMI AF: 0.261

Gnomad AMR AF: 0.0788

Gnomad ASJ AF: 0.0778

Gnomad EAS AF: 0.000769

Gnomad SAS AF: 0.0513

Gnomad FIN AF: 0.173

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.128

Gnomad OTH AF: 0.0840

GnomAD2 exomes AF: 0.0914 AC: 22982 AN: 251464 AF XY: 0.0942

Gnomad AFR exome AF: 0.0218

Gnomad AMR exome AF: 0.0519

Gnomad ASJ exome AF: 0.0811

Gnomad EAS exome AF: 0.000544

Gnomad FIN exome AF: 0.162

Gnomad NFE exome AF: 0.125

Gnomad OTH exome AF: 0.0981

GnomAD4 exome AF: 0.118 AC: 172003 AN: 1461834 Hom.: 11073 Cov.: 33 AF XY: 0.116 AC XY: 84329 AN XY: 727220

African (AFR) AF: 0.0185 AC: 620 AN: 33480

American (AMR) AF: 0.0538 AC: 2408 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0830 AC: 2170 AN: 26136

East Asian (EAS) AF: 0.000202 AC: 8 AN: 39700

South Asian (SAS) AF: 0.0565 AC: 4875 AN: 86256

European-Finnish (FIN) AF: 0.153 AC: 8190 AN: 53420

Middle Eastern (MID) AF: 0.0563 AC: 324 AN: 5754

European-Non Finnish (NFE) AF: 0.132 AC: 147330 AN: 1111978

Other (OTH) AF: 0.101 AC: 6078 AN: 60386

GnomAD4 genome AF: 0.0896 AC: 13642 AN: 152300 Hom.: 878 Cov.: 33 AF XY: 0.0916 AC XY: 6820 AN XY: 74468

African (AFR) AF: 0.0235 AC: 978 AN: 41582

American (AMR) AF: 0.0787 AC: 1204 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0778 AC: 270 AN: 3470

East Asian (EAS) AF: 0.000771 AC: 4 AN: 5188

South Asian (SAS) AF: 0.0517 AC: 250 AN: 4832

European-Finnish (FIN) AF: 0.173 AC: 1828 AN: 10596

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.128 AC: 8676 AN: 68016

Other (OTH) AF: 0.0832 AC: 176 AN: 2116

Alfa AF: 0.115 Hom.: 833

Bravo AF: 0.0793

TwinsUK AF: 0.132 AC: 490

ALSPAC AF: 0.131 AC: 503

ESP6500AA AF: 0.0277 AC: 122

ESP6500EA AF: 0.120 AC: 1032

ExAC AF: 0.0903 AC: 10963

Asia WGS AF: 0.0210 AC: 75 AN: 3478

EpiCase AF: 0.121

EpiControl AF: 0.123

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Hereditary spastic paraplegia 15 (2)
-	-	2	not specified (2)
-	-	1	not provided (1)
-	-	1	Spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	12
DANN	Benign	0.93
DEOGEN2	Benign	0.0090	T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.40
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.52	T
MetaRNN	Benign	0.0013	T
MetaSVM	Benign	-1.0	T
PhyloP100		1.3
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.10	N
REVEL	Benign	0.044
Sift	Benign	0.38	T
Sift4G	Benign	0.27	T
Polyphen		0.041	B
Vest4		0.13
MutPred		0.14		Gain of glycosylation at T898 (P = 0.0402)
MPC		0.15
ClinPred		0.0027	T
GERP RS		2.4
gMVP		0.30
Mutation Taster		=100/0	polymorphism (auto)

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: rs17192170; hg19: chr14-68257352; COSMIC: COSV61326077;