rs34952009

Variant names:

• chr14-67767816-C-A
• rs34952009
• NM_015346.4:c.5678G>T
• ZFYVE26 p.Ser1893Ile

Your query was ambiguous. Multiple possible variants found:

• chr14-67767816-C-A
• chr14-67767816-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.5678G>T​(p.Ser1893Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00821 in 1,614,132 control chromosomes in the GnomAD database, including 71 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1893G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0070 (5 hom., cov: 31)
  • Exomes 𝑓: 0.0083 (66 hom.)
• Consequence: ZFYVE26 NM_015346.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 0.740
• Publications: 10 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: Orphanet, G2P, Myriad Women's Health, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005324453).
• BP6: Variant 14-67767816-C-A is Benign according to our data. Variant chr14-67767816-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 188139.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00701 (1068/152256) while in subpopulation NFE AF = 0.00913 (621/68030). AF 95% confidence interval is 0.00853. There are 5 homozygotes in GnomAd4. There are 527 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 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.5678G>T	p.Ser1893Ile	missense	Exon 31 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.5678G>T	p.Ser1893Ile	missense	Exon 31 of 42	ENSP00000251119.5	Q68DK2-1
	ZFYVE26	ENST00000555452.1	TSL:1	c.5678G>T	p.Ser1893Ile	missense	Exon 31 of 35	ENSP00000450603.1	G3V2D8
	ZFYVE26	ENST00000554523.5	TSL:1	n.5815G>T		non_coding_transcript_exon	Exon 31 of 41

Frequencies

GnomAD3 genomes AF: 0.00702 AC: 1068 AN: 152138 Hom.: 5 Cov.: 31

Gnomad AFR AF: 0.00152

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.00543

Gnomad ASJ AF: 0.0184

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.0192

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00914

Gnomad OTH AF: 0.00860

GnomAD2 exomes AF: 0.00863 AC: 2170 AN: 251332 AF XY: 0.00869

Gnomad AFR exome AF: 0.00148

Gnomad AMR exome AF: 0.00546

Gnomad ASJ exome AF: 0.0181

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0195

Gnomad NFE exome AF: 0.0102

Gnomad OTH exome AF: 0.0111

GnomAD4 exome AF: 0.00833 AC: 12177 AN: 1461876 Hom.: 66 Cov.: 30 AF XY: 0.00841 AC XY: 6116 AN XY: 727236

African (AFR) AF: 0.00137 AC: 46 AN: 33480

American (AMR) AF: 0.00577 AC: 258 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0194 AC: 508 AN: 26136

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

South Asian (SAS) AF: 0.00385 AC: 332 AN: 86258

European-Finnish (FIN) AF: 0.0191 AC: 1020 AN: 53418

Middle Eastern (MID) AF: 0.00919 AC: 53 AN: 5768

European-Non Finnish (NFE) AF: 0.00849 AC: 9438 AN: 1111998

Other (OTH) AF: 0.00863 AC: 521 AN: 60396

GnomAD4 genome AF: 0.00701 AC: 1068 AN: 152256 Hom.: 5 Cov.: 31 AF XY: 0.00708 AC XY: 527 AN XY: 74440

African (AFR) AF: 0.00154 AC: 64 AN: 41536

American (AMR) AF: 0.00543 AC: 83 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0184 AC: 64 AN: 3472

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

South Asian (SAS) AF: 0.00187 AC: 9 AN: 4824

European-Finnish (FIN) AF: 0.0192 AC: 203 AN: 10598

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00913 AC: 621 AN: 68030

Other (OTH) AF: 0.00851 AC: 18 AN: 2114

Alfa AF: 0.00870 Hom.: 13

Bravo AF: 0.00621

Asia WGS AF: 0.00173 AC: 7 AN: 3478

EpiCase AF: 0.00981

EpiControl AF: 0.0104

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	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
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.026	T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.34
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.72	T
MetaRNN	Benign	0.0053	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.74
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.72	N
REVEL	Benign	0.075
Sift	Benign	0.23	T
Sift4G	Uncertain	0.046	D
gMVP		0.37
Mutation Taster		=96/4	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs34952009;

hg19: chr14-68234533;

COSMIC: COSV61333087;