rs34296097

Variant names:

• chr14-67783395-G-A
• rs34296097
• NM_015346.4:c.3757C>T

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.3757C>T​(p.Leu1253Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00956 in 1,614,152 control chromosomes in the GnomAD database, including 479 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.033 (219 hom., cov: 32)
  • Exomes 𝑓: 0.0071 (260 hom.)
• Consequence: ZFYVE26 NM_015346.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.916
• Publications: 3 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=-0.83).
• BP6: Variant 14-67783395-G-A is Benign according to our data. Variant chr14-67783395-G-A is described in ClinVar as Benign. ClinVar VariationId is 313905.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.916 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0985 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.3757C>T	p.Leu1253Leu	synonymous	Exon 21 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.3757C>T	p.Leu1253Leu	synonymous	Exon 21 of 42	ENSP00000251119.5	Q68DK2-1
	ZFYVE26	ENST00000555452.1	TSL:1	c.3757C>T	p.Leu1253Leu	synonymous	Exon 21 of 35	ENSP00000450603.1	G3V2D8
	ZFYVE26	ENST00000554523.5	TSL:1	n.3894C>T		non_coding_transcript_exon	Exon 21 of 41

Frequencies

GnomAD3 genomes AF: 0.0327 AC: 4980 AN: 152148 Hom.: 215 Cov.: 32

Gnomad AFR AF: 0.101

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0198

Gnomad ASJ AF: 0.0196

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00311

Gnomad FIN AF: 0.000376

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.00459

Gnomad OTH AF: 0.0435

GnomAD2 exomes AF: 0.0127 AC: 3186 AN: 251326 AF XY: 0.0106

Gnomad AFR exome AF: 0.105

Gnomad AMR exome AF: 0.0151

Gnomad ASJ exome AF: 0.0196

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00466

Gnomad OTH exome AF: 0.0158

GnomAD4 exome AF: 0.00713 AC: 10428 AN: 1461886 Hom.: 260 Cov.: 34 AF XY: 0.00681 AC XY: 4953 AN XY: 727242

African (AFR) AF: 0.112 AC: 3737 AN: 33480

American (AMR) AF: 0.0164 AC: 732 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0196 AC: 513 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00390 AC: 336 AN: 86258

European-Finnish (FIN) AF: 0.0000936 AC: 5 AN: 53418

Middle Eastern (MID) AF: 0.0222 AC: 128 AN: 5768

European-Non Finnish (NFE) AF: 0.00376 AC: 4178 AN: 1112006

Other (OTH) AF: 0.0132 AC: 798 AN: 60396

GnomAD4 genome AF: 0.0329 AC: 5008 AN: 152266 Hom.: 219 Cov.: 32 AF XY: 0.0316 AC XY: 2350 AN XY: 74452

African (AFR) AF: 0.101 AC: 4195 AN: 41510

American (AMR) AF: 0.0197 AC: 302 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0196 AC: 68 AN: 3472

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

South Asian (SAS) AF: 0.00311 AC: 15 AN: 4826

European-Finnish (FIN) AF: 0.000376 AC: 4 AN: 10628

Middle Eastern (MID) AF: 0.0714 AC: 21 AN: 294

European-Non Finnish (NFE) AF: 0.00459 AC: 312 AN: 68030

Other (OTH) AF: 0.0430 AC: 91 AN: 2114

Alfa AF: 0.0174 Hom.: 58

Bravo AF: 0.0378

Asia WGS AF: 0.00866 AC: 30 AN: 3478

EpiCase AF: 0.00812

EpiControl AF: 0.00634

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Hereditary spastic paraplegia 15 (2)
-	-	2	not specified (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	-0.83
CADD	Benign	2.3
DANN	Benign	0.38
PhyloP100		0.92
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: rs34296097; hg19: chr14-68250112;