rs199630965

chr14-67806571-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM2 BP4_Strong BP6_Very_Strong BS1

The NM_015346.4(ZFYVE26):c.991A>G(p.Asn331Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000134 in 1,614,208 control chromosomes in the GnomAD database, including 1 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 (★★). Synonymous variant affecting the same amino acid position (i.e. N331N) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00014 (1 hom.)
• Consequence: ZFYVE26 NM_015346.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 3.37

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0059517324).
• BP6: Variant 14-67806571-T-C is Benign according to our data. Variant chr14-67806571-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 215891.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.000138 (202/1461880) while in subpopulation AMR AF= 0.00445 (199/44724). AF 95% confidence interval is 0.00394. There are 1 homozygotes in gnomad4_exome. There are 78 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZFYVE26	NM_015346.4	c.991A>G	p.Asn331Asp	missense_variant	6/42	ENST00000347230.9
ZFYVE26	XM_047431173.1	c.991A>G	p.Asn331Asp	missense_variant	6/42
ZFYVE26	XM_011536609.3	c.991A>G	p.Asn331Asp	missense_variant	6/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZFYVE26	ENST00000347230.9	c.991A>G	p.Asn331Asp	missense_variant	6/42	1	NM_015346.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152210 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000763 AC: 192 AN: 251480 Hom.: 0 AF XY: 0.000537 AC XY: 73 AN XY: 135918

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00552

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000138 AC: 202 AN: 1461880 Hom.: 1 Cov.: 31 AF XY: 0.000107 AC XY: 78 AN XY: 727238

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00445

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000919 AC: 14 AN: 152328 Hom.: 0 Cov.: 33 AF XY: 0.000107 AC XY: 8 AN XY: 74496

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000915

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000554 Hom.: 0

Bravo AF: 0.000317

ExAC AF: 0.000815 AC: 99

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 05, 2016

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Spastic paraplegia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 24, 2024

- -

Hereditary spastic paraplegia 15 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 07, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.67
Cadd	Benign	22
Dann	Benign	0.87
Eigen	Benign	-0.17
Eigen_PC	Benign	0.019
FATHMM_MKL	Benign	0.75	D
M_CAP	Benign	0.0070	T
MetaRNN	Benign	0.0060	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.99	N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.75	N;N
REVEL	Benign	0.044
Sift	Benign	0.29	T;T
Sift4G	Benign	0.46	T;T
Polyphen		0.010	.;B
Vest4		0.16
MVP		0.18
MPC		0.21
ClinPred		0.019	T
GERP RS		4.7
gMVP		0.031

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

Publications

LitVar

Other links and lift over

dbSNP: rs199630965; hg19: chr14-68273288;