ZFYVE26 p.Thr799Met

Variant names:

• chr14-67794176-G-A
• rs200179480
• NM_015346.4:c.2396C>T
• ZFYVE26 p.Thr799Met

GermlineCancer (beta)

Variant summary

Our verdict is Likely benign.

-2 Likely Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -2 classification points (ACMG Germline Pathogenicity v2019). PM2_SupportingBP4_ModerateBP6

The NM_015346.4(ZFYVE26):c.2396C>T (p.Thr799Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.000117 (AC=189) in the gnomAD database across 1,614,178 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.000118. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (no review stars). Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.T799= (synonymous): Likely_benign (ClinVar VariationId 2911541, 1 star); p.T799= (synonymous): Likely_benign (ClinVar VariationId 1145345, 2 stars) This exact variant is curated in the UniProt human variants database as Uncertain Significance; it is also listed as a COSMIC curated somatic variant.

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: ZFYVE26 NM_015346.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 6.14
• Publications: 1 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, G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia, Myriad Women's Health

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Likely_benign. The variant received -2 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Rare in gnomAD for AR/unknown gene (popmax AF below threshold) — PM2 Supporting; GnomAD popmax AF = 0.000118 — borderline rare for AR gene (threshold 0.001) — PM2 supporting.
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Moderate).
	BP6Reputable source reports benign		ClinVar 0-star benign — supporting (BP6); ClinVar germline classification: Benign/Likely Benign, 0 star(s).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_015346.4. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	ZFYVE26 NM_015346.4	MANE Select	c.2396C>T p.Thr799Met	missense	Exon 13 of 42	Prot: NP_056161.2

ZFYVE26 NM_015346.4

MANE Select

HGVSc / HGVSpc.2396C>Tp.Thr799Met

Exon rankExon 13 of 42

missense

Prot: NP_056161.2

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	ZFYVE26 ENST00000347230.9	TSL:1MANE Select	c.2396C>T p.Thr799Met	missense	Exon 13 of 42	Prot: ENSP00000251119.5 UniProt:
	ZFYVE26 ENST00000555452.1	TSL:1	c.2396C>T p.Thr799Met	missense	Exon 13 of 35	Prot: ENSP00000450603.1 UniProt:
	ZFYVE26 ENST00000554557.5	TSL:1	n.*693C>T	3_prime_UTR	Exon 11 of 40	Prot: ENSP00000450431.1 UniProt:

ZFYVE26 ENST00000347230.9

TSL:1MANE Select

HGVSc / HGVSpc.2396C>Tp.Thr799Met

Exon rankExon 13 of 42

missense

Prot: ENSP00000251119.5UniProt: Q68DK2-1

ZFYVE26 ENST00000555452.1

TSL:1

HGVSc / HGVSpc.2396C>Tp.Thr799Met

Exon rankExon 13 of 35

missense

Prot: ENSP00000450603.1UniProt: G3V2D8

ZFYVE26 ENST00000554557.5

TSL:1

HGVSc / HGVSpn.*693C>T

Exon rankExon 11 of 40

3_prime_UTR

Prot: ENSP00000450431.1UniProt: G3V230

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.000138	AC:21	Hom:0	AN:152210	Cov:32
GnomAD2 exomes	AF: 0.000247	AC:62	Hom:	AN:251488	Cov:
GnomAD4 exome	AF: 0.000115	AC:168	Hom:0	AN:1461850	Cov:31
GnomAD4 genome	AF: 0.000138	AC:21	Hom:0	AN:152328	Cov:32
TOPMed (Bravo)	AF: 0.000121	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.000424	AC:20	Hom:0	AN:47210	Cov:
Local & regional cohorts 3 sources Population-specific and national genomic databases
ChinaMAP Phase 1	AF: 0.000394	AC:	Hom:	AN:	Cov:
ESP6500 (Exome Variant Server)	AF: 0.000154	AC:2	Hom:	AN:13006	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.000335	AC:3	Hom:0	AN:8960	Cov:

Showing 9 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.0000900 *	1	11112	0.000114 *	2	17618
BipEx(Bipolar disorder (including schizoaffective))	0.0000352	1	28420	0.00	0	28844
Epi25(Epilepsy)	0.0000715	3	41956	0.000150	10	66882
SCHEMA(Schizophrenia)	0.000169	19	112744	0.000184	35	189738

Showing 4 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	25
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.30
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Benign	0.057	T
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.99	D
FuncVEP CTI	Benign	0.0081
GPN-Star LLR	N/A	-4.0
GPN-Star score	N/A	3.7
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.017	T
MetaSVM	Benign	-0.81	T
Mutation Taster	N/A	78/22	polymorphism
PhyloP100	Uncertain	6.1
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.18
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
VESM-3B	Benign	-5.3

Showing 25 of 25 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.050
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs200179480;

hg19: chr14-68260893;

COSMIC: COSV100720658;

COSMIC: COSV100720658;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

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