14-67782782-C-T

Variant names:

• chr14-67782782-C-T
• rs2235967
• NM_015346.4:c.4370G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_015346.4(ZFYVE26):​c.4370G>A​(p.Cys1457Tyr) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.313 in 1,613,970 control chromosomes in the GnomAD database, including 85,746 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict 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 Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C1457S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.24 (5736 hom., cov: 32)
  • Exomes 𝑓: 0.32 (80010 hom.)
• Consequence: ZFYVE26 NM_015346.4 missense, splice_region
• Scores: Splicing: ADA: 0.00006575
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 2.73
• Publications: 34 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 (MetaRNN=0.0037769675).
• BP6: Variant 14-67782782-C-T is Benign according to our data. Variant chr14-67782782-C-T is described in ClinVar as Benign. ClinVar VariationId is 130782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.347 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.4370G>A	p.Cys1457Tyr	missense splice_region	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.4370G>A	p.Cys1457Tyr	missense splice_region	Exon 21 of 42	ENSP00000251119.5
	ZFYVE26	ENST00000555452.1	TSL:1	c.4370G>A	p.Cys1457Tyr	missense splice_region	Exon 21 of 35	ENSP00000450603.1
	ZFYVE26	ENST00000554523.5	TSL:1	n.4507G>A		splice_region non_coding_transcript_exon	Exon 21 of 41

Frequencies

GnomAD3 genomes AF: 0.244 AC: 37035 AN: 152080 Hom.: 5739 Cov.: 32

Gnomad AFR AF: 0.0797

Gnomad AMI AF: 0.349

Gnomad AMR AF: 0.217

Gnomad ASJ AF: 0.417

Gnomad EAS AF: 0.0225

Gnomad SAS AF: 0.225

Gnomad FIN AF: 0.278

Gnomad MID AF: 0.370

Gnomad NFE AF: 0.351

Gnomad OTH AF: 0.253

GnomAD2 exomes AF: 0.262 AC: 65695 AN: 251120 AF XY: 0.270

Gnomad AFR exome AF: 0.0719

Gnomad AMR exome AF: 0.174

Gnomad ASJ exome AF: 0.411

Gnomad EAS exome AF: 0.0225

Gnomad FIN exome AF: 0.283

Gnomad NFE exome AF: 0.347

Gnomad OTH exome AF: 0.304

GnomAD4 exome AF: 0.320 AC: 468192 AN: 1461772 Hom.: 80010 Cov.: 56 AF XY: 0.319 AC XY: 231801 AN XY: 727190

African (AFR) AF: 0.0669 AC: 2240 AN: 33480

American (AMR) AF: 0.181 AC: 8075 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.402 AC: 10510 AN: 26128

East Asian (EAS) AF: 0.0246 AC: 975 AN: 39700

South Asian (SAS) AF: 0.218 AC: 18798 AN: 86258

European-Finnish (FIN) AF: 0.285 AC: 15206 AN: 53338

Middle Eastern (MID) AF: 0.331 AC: 1910 AN: 5768

European-Non Finnish (NFE) AF: 0.353 AC: 392130 AN: 1111982

Other (OTH) AF: 0.304 AC: 18348 AN: 60394

GnomAD4 genome AF: 0.243 AC: 37024 AN: 152198 Hom.: 5736 Cov.: 32 AF XY: 0.238 AC XY: 17681 AN XY: 74402

African (AFR) AF: 0.0795 AC: 3304 AN: 41546

American (AMR) AF: 0.217 AC: 3314 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.417 AC: 1447 AN: 3472

East Asian (EAS) AF: 0.0226 AC: 117 AN: 5178

South Asian (SAS) AF: 0.225 AC: 1086 AN: 4822

European-Finnish (FIN) AF: 0.278 AC: 2945 AN: 10594

Middle Eastern (MID) AF: 0.378 AC: 111 AN: 294

European-Non Finnish (NFE) AF: 0.351 AC: 23856 AN: 67980

Other (OTH) AF: 0.249 AC: 526 AN: 2112

Alfa AF: 0.311 Hom.: 34873

Bravo AF: 0.231

TwinsUK AF: 0.355 AC: 1318

ALSPAC AF: 0.362 AC: 1395

ESP6500AA AF: 0.0874 AC: 385

ESP6500EA AF: 0.354 AC: 3042

ExAC AF: 0.263 AC: 31934

Asia WGS AF: 0.134 AC: 467 AN: 3476

EpiCase AF: 0.358

EpiControl AF: 0.356

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	3	Hereditary spastic paraplegia 15 (3)
-	-	1	Hereditary spastic paraplegia (1)
-	-	1	not provided (1)
-	-	1	Spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	21
DANN	Benign	0.40
DEOGEN2	Benign	0.018	T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.70	T
MetaRNN	Benign	0.0038	T
MetaSVM	Benign	-0.91	T
PhyloP100		2.7
PrimateAI	Benign	0.37	T
PROVEAN	Benign	0.93	N
REVEL	Benign	0.047
Sift	Benign	1.0	T
Sift4G	Benign	0.46	T
Polyphen		0.0	B
Vest4		0.15
MPC		0.28
ClinPred		0.0031	T
GERP RS		2.5
gMVP		0.13
Mutation Taster		=93/7	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000066
dbscSNV1_RF	Benign	0.042
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: rs2235967; hg19: chr14-68249499; COSMIC: COSV61326255; COSMIC: COSV61326255;