rs201771769

Variant names:

• chr14-67748644-C-G
• rs201771769
• NM_015346.4:c.7417-5G>C

Your query was ambiguous. Multiple possible variants found:

• chr14-67748644-C-G
• chr14-67748644-C-A
• chr14-67748644-C-T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_015346.4(ZFYVE26):​c.7417-5G>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00533 in 1,613,792 control chromosomes in the GnomAD database, including 59 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0038 (7 hom., cov: 33)
  • Exomes 𝑓: 0.0055 (52 hom.)
• Consequence: ZFYVE26 NM_015346.4 splice_region, intron
• Scores: Splicing: ADA: 0.00008164
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: -0.492
• Publications: 0 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 14-67748644-C-G is Benign according to our data. Variant chr14-67748644-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 215520.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00378 (576/152352) while in subpopulation SAS AF = 0.0207 (100/4826). AF 95% confidence interval is 0.0174. There are 7 homozygotes in GnomAd4. There are 293 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 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.7417-5G>C		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.7417-5G>C		splice_region intron	N/A	ENSP00000251119.5	Q68DK2-1
	ZFYVE26	ENST00000554523.5	TSL:1	n.8172-5G>C		splice_region intron	N/A
	ZFYVE26	ENST00000554557.5	TSL:1	n.*5395-5G>C		splice_region intron	N/A	ENSP00000450431.1	G3V230

Frequencies

GnomAD3 genomes AF: 0.00379 AC: 577 AN: 152234 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.000724

Gnomad AMI AF: 0.0285

Gnomad AMR AF: 0.00445

Gnomad ASJ AF: 0.0130

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0207

Gnomad FIN AF: 0.000941

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00417

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00564 AC: 1380 AN: 244894 AF XY: 0.00654

Gnomad AFR exome AF: 0.00101

Gnomad AMR exome AF: 0.00386

Gnomad ASJ exome AF: 0.0101

Gnomad EAS exome AF: 0.0000547

Gnomad FIN exome AF: 0.00120

Gnomad NFE exome AF: 0.00458

Gnomad OTH exome AF: 0.00531

GnomAD4 exome AF: 0.00549 AC: 8030 AN: 1461440 Hom.: 52 Cov.: 30 AF XY: 0.00594 AC XY: 4320 AN XY: 726980

African (AFR) AF: 0.000807 AC: 27 AN: 33474

American (AMR) AF: 0.00416 AC: 186 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00983 AC: 257 AN: 26132

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39698

South Asian (SAS) AF: 0.0182 AC: 1571 AN: 86230

European-Finnish (FIN) AF: 0.00141 AC: 75 AN: 53054

Middle Eastern (MID) AF: 0.00919 AC: 53 AN: 5766

European-Non Finnish (NFE) AF: 0.00494 AC: 5497 AN: 1111984

Other (OTH) AF: 0.00599 AC: 362 AN: 60386

GnomAD4 genome AF: 0.00378 AC: 576 AN: 152352 Hom.: 7 Cov.: 33 AF XY: 0.00393 AC XY: 293 AN XY: 74514

African (AFR) AF: 0.000722 AC: 30 AN: 41580

American (AMR) AF: 0.00444 AC: 68 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0130 AC: 45 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.0207 AC: 100 AN: 4826

European-Finnish (FIN) AF: 0.000941 AC: 10 AN: 10628

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

European-Non Finnish (NFE) AF: 0.00417 AC: 284 AN: 68030

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.00384 Hom.: 2

Bravo AF: 0.00363

Asia WGS AF: 0.00866 AC: 30 AN: 3478

EpiCase AF: 0.00622

EpiControl AF: 0.00611

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	6.4
DANN	Benign	0.76
PhyloP100		-0.49
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000082
dbscSNV1_RF	Benign	0.056
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: rs201771769; hg19: chr14-68215361;