NM_015346.4:c.2332+7delT

Variant names:

• chr14-67797664-CA-C
• rs145183291
• NM_015346.4:c.2332+7delT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_015346.4(ZFYVE26):​c.2332+7delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0155 in 1,613,816 control chromosomes in the GnomAD database, including 355 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.026 (82 hom., cov: 32)
  • Exomes 𝑓: 0.014 (273 hom.)
• Consequence: ZFYVE26 NM_015346.4 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.296
• 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 -16 ACMG points.

• BP6: Variant 14-67797664-CA-C is Benign according to our data. Variant chr14-67797664-CA-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 313914.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0578 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.2332+7delT		splice_region intron	N/A	NP_056161.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZFYVE26	ENST00000347230.9	TSL:1 MANE Select	c.2332+7delT		splice_region intron	N/A	ENSP00000251119.5	Q68DK2-1
	ZFYVE26	ENST00000555452.1	TSL:1	c.2332+7delT		splice_region intron	N/A	ENSP00000450603.1	G3V2D8
	ZFYVE26	ENST00000557366.5	TSL:1	n.2385delT		non_coding_transcript_exon	Exon 11 of 11

Frequencies

GnomAD3 genomes AF: 0.0255 AC: 3882 AN: 152140 Hom.: 82 Cov.: 32

Gnomad AFR AF: 0.0596

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00968

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.0519

Gnomad SAS AF: 0.0159

Gnomad FIN AF: 0.00726

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0114

Gnomad OTH AF: 0.0230

GnomAD2 exomes AF: 0.0169 AC: 4231 AN: 251080 AF XY: 0.0157

Gnomad AFR exome AF: 0.0631

Gnomad AMR exome AF: 0.00535

Gnomad ASJ exome AF: 0.00149

Gnomad EAS exome AF: 0.0514

Gnomad FIN exome AF: 0.00579

Gnomad NFE exome AF: 0.0123

Gnomad OTH exome AF: 0.0114

GnomAD4 exome AF: 0.0145 AC: 21186 AN: 1461558 Hom.: 273 Cov.: 30 AF XY: 0.0144 AC XY: 10454 AN XY: 727052

African (AFR) AF: 0.0582 AC: 1949 AN: 33478

American (AMR) AF: 0.00537 AC: 240 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00111 AC: 29 AN: 26120

East Asian (EAS) AF: 0.0606 AC: 2407 AN: 39694

South Asian (SAS) AF: 0.0158 AC: 1365 AN: 86182

European-Finnish (FIN) AF: 0.00723 AC: 386 AN: 53400

Middle Eastern (MID) AF: 0.00936 AC: 54 AN: 5768

European-Non Finnish (NFE) AF: 0.0124 AC: 13802 AN: 1111830

Other (OTH) AF: 0.0158 AC: 954 AN: 60378

GnomAD4 genome AF: 0.0256 AC: 3896 AN: 152258 Hom.: 82 Cov.: 32 AF XY: 0.0251 AC XY: 1865 AN XY: 74438

African (AFR) AF: 0.0598 AC: 2483 AN: 41538

American (AMR) AF: 0.00960 AC: 147 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00259 AC: 9 AN: 3470

East Asian (EAS) AF: 0.0522 AC: 270 AN: 5174

South Asian (SAS) AF: 0.0162 AC: 78 AN: 4828

European-Finnish (FIN) AF: 0.00726 AC: 77 AN: 10610

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0114 AC: 778 AN: 68012

Other (OTH) AF: 0.0227 AC: 48 AN: 2112

Alfa AF: 0.00393 Hom.: 0

Bravo AF: 0.0277

Asia WGS AF: 0.0330 AC: 113 AN: 3478

EpiCase AF: 0.0104

EpiControl AF: 0.0115

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.30
Mutation Taster		=84/16	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs145183291; hg19: chr14-68264381;