chr14-67790768-C-T

Variant names:

• chr14-67790768-C-T
• rs7143196
• NM_015346.4:c.2559G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_015346.4(ZFYVE26):​c.2559G>A​(p.Leu853Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.184 in 1,613,194 control chromosomes in the GnomAD database, including 30,501 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L853L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.14 (1964 hom., cov: 32)
  • Exomes 𝑓: 0.19 (28537 hom.)
• Consequence: ZFYVE26 NM_015346.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.0140
• Publications: 17 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 14-67790768-C-T is Benign according to our data. Variant chr14-67790768-C-T is described in ClinVar as Benign. ClinVar VariationId is 130777.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.014 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.209 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZFYVE26	NM_015346.4	MANE Select	c.2559G>A	p.Leu853Leu	synonymous	Exon 15 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.2559G>A	p.Leu853Leu	synonymous	Exon 15 of 42	ENSP00000251119.5	Q68DK2-1
	ZFYVE26	ENST00000555452.1	TSL:1	c.2559G>A	p.Leu853Leu	synonymous	Exon 15 of 35	ENSP00000450603.1	G3V2D8
	ZFYVE26	ENST00000554523.5	TSL:1	n.2696G>A		non_coding_transcript_exon	Exon 15 of 41

Frequencies

GnomAD3 genomes AF: 0.139 AC: 21131 AN: 152092 Hom.: 1965 Cov.: 32

Gnomad AFR AF: 0.0429

Gnomad AMI AF: 0.156

Gnomad AMR AF: 0.101

Gnomad ASJ AF: 0.195

Gnomad EAS AF: 0.0167

Gnomad SAS AF: 0.0644

Gnomad FIN AF: 0.181

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.212

Gnomad OTH AF: 0.125

GnomAD2 exomes AF: 0.145 AC: 36452 AN: 251408 AF XY: 0.147

Gnomad AFR exome AF: 0.0363

Gnomad AMR exome AF: 0.0960

Gnomad ASJ exome AF: 0.193

Gnomad EAS exome AF: 0.0176

Gnomad FIN exome AF: 0.183

Gnomad NFE exome AF: 0.204

Gnomad OTH exome AF: 0.160

GnomAD4 exome AF: 0.189 AC: 276408 AN: 1460984 Hom.: 28537 Cov.: 33 AF XY: 0.186 AC XY: 135534 AN XY: 726816

African (AFR) AF: 0.0323 AC: 1080 AN: 33470

American (AMR) AF: 0.0976 AC: 4367 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.188 AC: 4915 AN: 26120

East Asian (EAS) AF: 0.0218 AC: 867 AN: 39686

South Asian (SAS) AF: 0.0750 AC: 6469 AN: 86198

European-Finnish (FIN) AF: 0.187 AC: 9985 AN: 53398

Middle Eastern (MID) AF: 0.110 AC: 637 AN: 5766

European-Non Finnish (NFE) AF: 0.214 AC: 237787 AN: 1111256

Other (OTH) AF: 0.171 AC: 10301 AN: 60368

GnomAD4 genome AF: 0.139 AC: 21130 AN: 152210 Hom.: 1964 Cov.: 32 AF XY: 0.134 AC XY: 9955 AN XY: 74412

African (AFR) AF: 0.0428 AC: 1777 AN: 41546

American (AMR) AF: 0.101 AC: 1538 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.195 AC: 677 AN: 3470

East Asian (EAS) AF: 0.0168 AC: 87 AN: 5184

South Asian (SAS) AF: 0.0655 AC: 316 AN: 4828

European-Finnish (FIN) AF: 0.181 AC: 1916 AN: 10580

Middle Eastern (MID) AF: 0.133 AC: 39 AN: 294

European-Non Finnish (NFE) AF: 0.211 AC: 14377 AN: 67994

Other (OTH) AF: 0.124 AC: 261 AN: 2112

Alfa AF: 0.183 Hom.: 5452

Bravo AF: 0.128

Asia WGS AF: 0.0450 AC: 157 AN: 3478

EpiCase AF: 0.196

EpiControl AF: 0.194

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Hereditary spastic paraplegia 15 (2)
-	-	1	Hereditary spastic paraplegia (1)
-	-	1	not provided (1)
-	-	1	Spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	5.1
DANN	Benign	0.75
PhyloP100		-0.014
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs7143196; hg19: chr14-68257485; COSMIC: COSV61329350;