rs117367857

Variant names:

• chr14-67789528-C-T
• rs117367857
• NM_015346.4:c.2826G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_015346.4(ZFYVE26):​c.2826G>A​(p.Met942Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0112 in 1,614,134 control chromosomes in the GnomAD database, including 154 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0081 (15 hom., cov: 33)
  • Exomes 𝑓: 0.012 (139 hom.)
• Consequence: ZFYVE26 NM_015346.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -2.78
• Publications: 9 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=0.0047784746).
• BP6: Variant 14-67789528-C-T is Benign according to our data. Variant chr14-67789528-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 220334.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0081 (1234/152298) while in subpopulation NFE AF = 0.0128 (869/68024). AF 95% confidence interval is 0.0121. There are 15 homozygotes in GnomAd4. There are 557 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 15 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZFYVE26	NM_015346.4	MANE Select	c.2826G>A	p.Met942Ile	missense	Exon 16 of 42	NP_056161.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZFYVE26	ENST00000347230.9	TSL:1 MANE Select	c.2826G>A	p.Met942Ile	missense	Exon 16 of 42	ENSP00000251119.5
	ZFYVE26	ENST00000555452.1	TSL:1	c.2826G>A	p.Met942Ile	missense	Exon 16 of 35	ENSP00000450603.1
	ZFYVE26	ENST00000554523.5	TSL:1	n.2963G>A		non_coding_transcript_exon	Exon 16 of 41

Frequencies

GnomAD3 genomes AF: 0.00812 AC: 1235 AN: 152180 Hom.: 15 Cov.: 33

Gnomad AFR AF: 0.00217

Gnomad AMI AF: 0.0493

Gnomad AMR AF: 0.00465

Gnomad ASJ AF: 0.0306

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00331

Gnomad FIN AF: 0.00198

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0128

Gnomad OTH AF: 0.00670

GnomAD2 exomes AF: 0.00834 AC: 2091 AN: 250810 AF XY: 0.00834

Gnomad AFR exome AF: 0.00235

Gnomad AMR exome AF: 0.00408

Gnomad ASJ exome AF: 0.0283

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00176

Gnomad NFE exome AF: 0.0126

Gnomad OTH exome AF: 0.00980

GnomAD4 exome AF: 0.0115 AC: 16838 AN: 1461836 Hom.: 139 Cov.: 31 AF XY: 0.0112 AC XY: 8155 AN XY: 727216

African (AFR) AF: 0.00221 AC: 74 AN: 33480

American (AMR) AF: 0.00407 AC: 182 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0300 AC: 785 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00322 AC: 278 AN: 86258

European-Finnish (FIN) AF: 0.00204 AC: 109 AN: 53368

Middle Eastern (MID) AF: 0.0107 AC: 62 AN: 5768

European-Non Finnish (NFE) AF: 0.0132 AC: 14716 AN: 1112008

Other (OTH) AF: 0.0105 AC: 632 AN: 60396

GnomAD4 genome AF: 0.00810 AC: 1234 AN: 152298 Hom.: 15 Cov.: 33 AF XY: 0.00748 AC XY: 557 AN XY: 74482

African (AFR) AF: 0.00217 AC: 90 AN: 41556

American (AMR) AF: 0.00464 AC: 71 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0306 AC: 106 AN: 3468

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5184

South Asian (SAS) AF: 0.00311 AC: 15 AN: 4828

European-Finnish (FIN) AF: 0.00198 AC: 21 AN: 10616

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0128 AC: 869 AN: 68024

Other (OTH) AF: 0.00663 AC: 14 AN: 2112

Alfa AF: 0.0112 Hom.: 31

Bravo AF: 0.00786

TwinsUK AF: 0.0135 AC: 50

ALSPAC AF: 0.0130 AC: 50

ESP6500AA AF: 0.00295 AC: 13

ESP6500EA AF: 0.0145 AC: 125

ExAC AF: 0.00806 AC: 979

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.0132

EpiControl AF: 0.0122

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely 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	0.16
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.0010
DANN	Benign	0.81
DEOGEN2	Benign	0.0028	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.030	N
LIST_S2	Benign	0.28	T
MetaRNN	Benign	0.0048	T
MetaSVM	Benign	-1.0	T
PhyloP100		-2.8
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.080	N
REVEL	Benign	0.044
Sift	Benign	0.25	T
Sift4G	Benign	0.39	T
Polyphen		0.0	B
Vest4		0.19
MutPred		0.24		Loss of disorder (P = 0.1701)
MVP		0.099
MPC		0.18
ClinPred		0.0067	T
GERP RS		-11
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.35
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: rs117367857; hg19: chr14-68256245; COSMIC: COSV99052073;