14-67755116-G-A

Variant names:

• chr14-67755116-G-A
• rs35917338
• NM_015346.4:c.6921C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_015346.4(ZFYVE26):​c.6921C>T​(p.Ser2307Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00326 in 1,614,104 control chromosomes in the GnomAD database, including 174 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. S2307S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.018 (96 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (78 hom.)
• Consequence: ZFYVE26 NM_015346.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.534
• Publications: 1 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 14-67755116-G-A is Benign according to our data. Variant chr14-67755116-G-A is described in ClinVar as Benign. ClinVar VariationId is 241057.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.534 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0603 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.6921C>T	p.Ser2307Ser	synonymous	Exon 37 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.6921C>T	p.Ser2307Ser	synonymous	Exon 37 of 42	ENSP00000251119.5	Q68DK2-1
	ZFYVE26	ENST00000557306.1	TSL:1	c.459C>T	p.Ser153Ser	synonymous	Exon 3 of 7	ENSP00000452142.1	A0A2H2FF08
	ZFYVE26	ENST00000554523.5	TSL:1	n.7676C>T		non_coding_transcript_exon	Exon 36 of 41

Frequencies

GnomAD3 genomes AF: 0.0179 AC: 2719 AN: 152102 Hom.: 96 Cov.: 32

Gnomad AFR AF: 0.0621

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00681

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.0115

GnomAD2 exomes AF: 0.00488 AC: 1226 AN: 251456 AF XY: 0.00371

Gnomad AFR exome AF: 0.0670

Gnomad AMR exome AF: 0.00301

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000217

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000167

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.00173 AC: 2525 AN: 1461884 Hom.: 78 Cov.: 32 AF XY: 0.00148 AC XY: 1075 AN XY: 727242

African (AFR) AF: 0.0609 AC: 2040 AN: 33480

American (AMR) AF: 0.00358 AC: 160 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39700

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.0000638 AC: 71 AN: 1112010

Other (OTH) AF: 0.00402 AC: 243 AN: 60396

GnomAD4 genome AF: 0.0179 AC: 2732 AN: 152220 Hom.: 96 Cov.: 32 AF XY: 0.0171 AC XY: 1269 AN XY: 74424

African (AFR) AF: 0.0623 AC: 2585 AN: 41516

American (AMR) AF: 0.00680 AC: 104 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

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

European-Non Finnish (NFE) AF: 0.000279 AC: 19 AN: 68018

Other (OTH) AF: 0.0114 AC: 24 AN: 2114

Alfa AF: 0.00934 Hom.: 22

Bravo AF: 0.0207

Asia WGS AF: 0.00462 AC: 17 AN: 3476

EpiCase AF: 0.000218

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	7.8
DANN	Benign	0.69
PhyloP100		0.53
Mutation Taster		=98/2	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: rs35917338; hg19: chr14-68221833;