rs3742884

Variant names:

• chr14-67785217-G-A
• rs3742884
• NM_015346.4:c.3365C>T

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.3365C>T​(p.Ala1122Val) variant causes a missense change. The variant allele was found at a frequency of 0.0219 in 1,613,908 control chromosomes in the GnomAD database, including 844 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.045 (315 hom., cov: 32)
  • Exomes 𝑓: 0.019 (529 hom.)
• Consequence: ZFYVE26 NM_015346.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 3.67
• Publications: 14 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, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, G2P

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.001244396).
• BP6: Variant 14-67785217-G-A is Benign according to our data. Variant chr14-67785217-G-A is described in ClinVar as Benign. ClinVar VariationId is 130781.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.118 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.3365C>T	p.Ala1122Val	missense	Exon 19 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.3365C>T	p.Ala1122Val	missense	Exon 19 of 42	ENSP00000251119.5
	ZFYVE26	ENST00000555452.1	TSL:1	c.3365C>T	p.Ala1122Val	missense	Exon 19 of 35	ENSP00000450603.1
	ZFYVE26	ENST00000554523.5	TSL:1	n.3502C>T		non_coding_transcript_exon	Exon 19 of 41

Frequencies

GnomAD3 genomes AF: 0.0454 AC: 6914 AN: 152146 Hom.: 315 Cov.: 32

Gnomad AFR AF: 0.121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0195

Gnomad ASJ AF: 0.0115

Gnomad EAS AF: 0.0515

Gnomad SAS AF: 0.0195

Gnomad FIN AF: 0.00885

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0150

Gnomad OTH AF: 0.0421

GnomAD2 exomes AF: 0.0246 AC: 6152 AN: 249942 AF XY: 0.0228

Gnomad AFR exome AF: 0.127

Gnomad AMR exome AF: 0.0111

Gnomad ASJ exome AF: 0.0107

Gnomad EAS exome AF: 0.0516

Gnomad FIN exome AF: 0.00806

Gnomad NFE exome AF: 0.0161

Gnomad OTH exome AF: 0.0195

GnomAD4 exome AF: 0.0195 AC: 28484 AN: 1461644 Hom.: 529 Cov.: 32 AF XY: 0.0192 AC XY: 13992 AN XY: 727090

African (AFR) AF: 0.119 AC: 3996 AN: 33468

American (AMR) AF: 0.0114 AC: 509 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.0114 AC: 299 AN: 26134

East Asian (EAS) AF: 0.0602 AC: 2389 AN: 39698

South Asian (SAS) AF: 0.0194 AC: 1670 AN: 86250

European-Finnish (FIN) AF: 0.00929 AC: 496 AN: 53396

Middle Eastern (MID) AF: 0.0368 AC: 212 AN: 5768

European-Non Finnish (NFE) AF: 0.0157 AC: 17475 AN: 1111858

Other (OTH) AF: 0.0238 AC: 1438 AN: 60384

GnomAD4 genome AF: 0.0455 AC: 6927 AN: 152264 Hom.: 315 Cov.: 32 AF XY: 0.0440 AC XY: 3275 AN XY: 74438

African (AFR) AF: 0.121 AC: 5008 AN: 41534

American (AMR) AF: 0.0195 AC: 298 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0115 AC: 40 AN: 3470

East Asian (EAS) AF: 0.0519 AC: 268 AN: 5168

South Asian (SAS) AF: 0.0197 AC: 95 AN: 4828

European-Finnish (FIN) AF: 0.00885 AC: 94 AN: 10620

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0151 AC: 1024 AN: 68032

Other (OTH) AF: 0.0416 AC: 88 AN: 2114

Alfa AF: 0.0260 Hom.: 520

Bravo AF: 0.0506

TwinsUK AF: 0.0175 AC: 65

ALSPAC AF: 0.0143 AC: 55

ESP6500AA AF: 0.122 AC: 538

ESP6500EA AF: 0.0159 AC: 137

ExAC AF: 0.0275 AC: 3339

Asia WGS AF: 0.0360 AC: 125 AN: 3478

EpiCase AF: 0.0159

EpiControl AF: 0.0180

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	17
DANN	Benign	0.14
DEOGEN2	Benign	0.0089	T
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.71	T
MetaRNN	Benign	0.0012	T
MetaSVM	Benign	-0.99	T
PhyloP100		3.7
PrimateAI	Benign	0.37	T
PROVEAN	Benign	0.39	N
REVEL	Benign	0.088
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.012	B
Vest4		0.083
MPC		0.17
ClinPred		0.0085	T
GERP RS		2.7
gMVP		0.087
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs3742884; hg19: chr14-68251934; COSMIC: COSV61325742;