rs76728509

Variant names:

• chr14-67754215-G-A
• rs76728509
• NM_015346.4:c.6987-3C>T

Your query was ambiguous. Multiple possible variants found:

• chr14-67754215-G-A
• chr14-67754215-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_015346.4(ZFYVE26):​c.6987-3C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00578 in 1,614,168 control chromosomes in the GnomAD database, including 93 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (41 hom., cov: 32)
  • Exomes 𝑓: 0.0048 (52 hom.)
• Consequence: ZFYVE26 NM_015346.4 splice_region, intron
• Scores: Splicing: ADA: 0.0001415
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.389
• Publications: 2 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 (BayesDel_noAF=-0.81).
• BP6: Variant 14-67754215-G-A is Benign according to our data. Variant chr14-67754215-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 241058.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0151 (2301/152338) while in subpopulation AFR AF = 0.0432 (1798/41574). AF 95% confidence interval is 0.0416. There are 41 homozygotes in GnomAd4. There are 1055 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 41 AR gene

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.6987-3C>T		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.6987-3C>T		splice_region intron	N/A	ENSP00000251119.5
	ZFYVE26	ENST00000557306.1	TSL:1	c.525-3C>T		splice_region intron	N/A	ENSP00000452142.1
	ZFYVE26	ENST00000554523.5	TSL:1	n.7742-3C>T		splice_region intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0151 AC: 2298 AN: 152220 Hom.: 41 Cov.: 32

Gnomad AFR AF: 0.0433

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00766

Gnomad ASJ AF: 0.00951

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00393

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.00395

Gnomad OTH AF: 0.0206

GnomAD2 exomes AF: 0.00683 AC: 1716 AN: 251378 AF XY: 0.00619

Gnomad AFR exome AF: 0.0445

Gnomad AMR exome AF: 0.00598

Gnomad ASJ exome AF: 0.00982

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00180

Gnomad NFE exome AF: 0.00426

Gnomad OTH exome AF: 0.00879

GnomAD4 exome AF: 0.00481 AC: 7036 AN: 1461830 Hom.: 52 Cov.: 32 AF XY: 0.00485 AC XY: 3525 AN XY: 727212

African (AFR) AF: 0.0423 AC: 1416 AN: 33480

American (AMR) AF: 0.00599 AC: 268 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0117 AC: 307 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00436 AC: 376 AN: 86252

European-Finnish (FIN) AF: 0.00146 AC: 78 AN: 53416

Middle Eastern (MID) AF: 0.0256 AC: 147 AN: 5734

European-Non Finnish (NFE) AF: 0.00358 AC: 3976 AN: 1112002

Other (OTH) AF: 0.00775 AC: 468 AN: 60388

GnomAD4 genome AF: 0.0151 AC: 2301 AN: 152338 Hom.: 41 Cov.: 32 AF XY: 0.0142 AC XY: 1055 AN XY: 74490

African (AFR) AF: 0.0432 AC: 1798 AN: 41574

American (AMR) AF: 0.00765 AC: 117 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00951 AC: 33 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00393 AC: 19 AN: 4830

European-Finnish (FIN) AF: 0.00113 AC: 12 AN: 10626

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.00395 AC: 269 AN: 68028

Other (OTH) AF: 0.0203 AC: 43 AN: 2114

Alfa AF: 0.0123 Hom.: 20

Bravo AF: 0.0172

Asia WGS AF: 0.00404 AC: 14 AN: 3478

EpiCase AF: 0.00611

EpiControl AF: 0.00646

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.23
DANN	Benign	0.66
PhyloP100		-0.39
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00014
dbscSNV1_RF	Benign	0.0020
SpliceAI score (max)		0.10		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: rs76728509; hg19: chr14-68220932;