rs117228915

Variant names:

• chr14-67798418-G-A
• rs117228915
• NM_015346.4:c.1844C>T

Your query was ambiguous. Multiple possible variants found:

• chr14-67798418-G-A
• chr14-67798418-G-T

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.1844C>T​(p.Ser615Phe) variant causes a missense change. The variant allele was found at a frequency of 0.0109 in 1,613,474 control chromosomes in the GnomAD database, including 138 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0088 (11 hom., cov: 32)
  • Exomes 𝑓: 0.011 (127 hom.)
• Consequence: ZFYVE26 NM_015346.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 5.20
• Publications: 13 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=0.005330801).
• BP6: Variant 14-67798418-G-A is Benign according to our data. Variant chr14-67798418-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 219559.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 = 0.00884 (1346/152238) while in subpopulation NFE AF = 0.0139 (945/68028). AF 95% confidence interval is 0.0132. There are 11 homozygotes in GnomAd4. There are 606 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 11 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.1844C>T	p.Ser615Phe	missense	Exon 11 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.1844C>T	p.Ser615Phe	missense	Exon 11 of 42	ENSP00000251119.5
	ZFYVE26	ENST00000555452.1	TSL:1	c.1844C>T	p.Ser615Phe	missense	Exon 11 of 35	ENSP00000450603.1
	ZFYVE26	ENST00000554523.5	TSL:1	n.1981C>T		non_coding_transcript_exon	Exon 11 of 41

Frequencies

GnomAD3 genomes AF: 0.00886 AC: 1348 AN: 152122 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.00239

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00694

Gnomad ASJ AF: 0.0268

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00436

Gnomad FIN AF: 0.00538

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0139

Gnomad OTH AF: 0.00764

GnomAD2 exomes AF: 0.00927 AC: 2328 AN: 251238 AF XY: 0.00944

Gnomad AFR exome AF: 0.00277

Gnomad AMR exome AF: 0.00527

Gnomad ASJ exome AF: 0.0286

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00481

Gnomad NFE exome AF: 0.0134

Gnomad OTH exome AF: 0.0131

GnomAD4 exome AF: 0.0111 AC: 16249 AN: 1461236 Hom.: 127 Cov.: 39 AF XY: 0.0112 AC XY: 8147 AN XY: 726808

African (AFR) AF: 0.00212 AC: 71 AN: 33448

American (AMR) AF: 0.00642 AC: 287 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.0261 AC: 682 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.00395 AC: 341 AN: 86250

European-Finnish (FIN) AF: 0.00483 AC: 258 AN: 53410

Middle Eastern (MID) AF: 0.0170 AC: 98 AN: 5762

European-Non Finnish (NFE) AF: 0.0124 AC: 13742 AN: 1111504

Other (OTH) AF: 0.0128 AC: 770 AN: 60370

GnomAD4 genome AF: 0.00884 AC: 1346 AN: 152238 Hom.: 11 Cov.: 32 AF XY: 0.00814 AC XY: 606 AN XY: 74432

African (AFR) AF: 0.00238 AC: 99 AN: 41522

American (AMR) AF: 0.00693 AC: 106 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0268 AC: 93 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.00436 AC: 21 AN: 4818

European-Finnish (FIN) AF: 0.00538 AC: 57 AN: 10604

Middle Eastern (MID) AF: 0.0274 AC: 8 AN: 292

European-Non Finnish (NFE) AF: 0.0139 AC: 945 AN: 68028

Other (OTH) AF: 0.00756 AC: 16 AN: 2116

Alfa AF: 0.0124 Hom.: 43

Bravo AF: 0.00863

TwinsUK AF: 0.0113 AC: 42

ALSPAC AF: 0.0119 AC: 46

ESP6500AA AF: 0.00250 AC: 11

ESP6500EA AF: 0.0122 AC: 105

ExAC AF: 0.00892 AC: 1083

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.0154

EpiControl AF: 0.0154

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.36
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.041	T
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.83	T
MetaRNN	Benign	0.0053	T
MetaSVM	Benign	-0.84	T
PhyloP100		5.2
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.56	N
REVEL	Benign	0.14
Sift	Benign	0.086	T
Sift4G	Uncertain	0.017	D
Polyphen		0.98	D
Vest4		0.46
MVP		0.40
MPC		0.70
ClinPred		0.025	T
GERP RS		5.7
gMVP		0.41
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs117228915; hg19: chr14-68265135; COSMIC: COSV100720733; COSMIC: COSV100720733;