rs35018134

Variant names:

• chr14-67782955-G-A
• rs35018134
• NM_015346.4:c.4197C>T

Your query was ambiguous. Multiple possible variants found:

• chr14-67782955-G-A
• chr14-67782955-G-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_015346.4(ZFYVE26):​c.4197C>T​(p.Thr1399Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00315 in 1,614,192 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T1399T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0021 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0033 (19 hom.)
• Consequence: ZFYVE26 NM_015346.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:5
• Conservation: PhyloP100: 0.0870
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 14-67782955-G-A is Benign according to our data. Variant chr14-67782955-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 212640.
• BP7: Synonymous conserved (PhyloP=0.087 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00213 (324/152310) while in subpopulation SAS AF = 0.00394 (19/4828). AF 95% confidence interval is 0.00343. There are 2 homozygotes in GnomAd4. There are 158 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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.4197C>T	p.Thr1399Thr	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.4197C>T	p.Thr1399Thr	synonymous	Exon 21 of 42	ENSP00000251119.5	Q68DK2-1
	ZFYVE26	ENST00000555452.1	TSL:1	c.4197C>T	p.Thr1399Thr	synonymous	Exon 21 of 35	ENSP00000450603.1	G3V2D8
	ZFYVE26	ENST00000554523.5	TSL:1	n.4334C>T		non_coding_transcript_exon	Exon 21 of 41

Frequencies

GnomAD3 genomes AF: 0.00212 AC: 323 AN: 152192 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000676

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00373

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00381

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.00227 AC: 571 AN: 251366 AF XY: 0.00250

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.000520

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.000647

Gnomad NFE exome AF: 0.00351

Gnomad OTH exome AF: 0.00228

GnomAD4 exome AF: 0.00326 AC: 4765 AN: 1461882 Hom.: 19 Cov.: 34 AF XY: 0.00328 AC XY: 2383 AN XY: 727242

African (AFR) AF: 0.000448 AC: 15 AN: 33480

American (AMR) AF: 0.000604 AC: 27 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000765 AC: 2 AN: 26136

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

South Asian (SAS) AF: 0.00405 AC: 349 AN: 86258

European-Finnish (FIN) AF: 0.000618 AC: 33 AN: 53408

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5768

European-Non Finnish (NFE) AF: 0.00372 AC: 4141 AN: 1112012

Other (OTH) AF: 0.00316 AC: 191 AN: 60396

GnomAD4 genome AF: 0.00213 AC: 324 AN: 152310 Hom.: 2 Cov.: 32 AF XY: 0.00212 AC XY: 158 AN XY: 74478

African (AFR) AF: 0.000674 AC: 28 AN: 41568

American (AMR) AF: 0.000784 AC: 12 AN: 15308

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00394 AC: 19 AN: 4828

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10618

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

European-Non Finnish (NFE) AF: 0.00381 AC: 259 AN: 68028

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.00216 Hom.: 0

Bravo AF: 0.00195

EpiCase AF: 0.00371

EpiControl AF: 0.00350

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	2.6
DANN	Benign	0.49
PhyloP100		0.087
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism

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: rs35018134; hg19: chr14-68249672;