NM_021260.4:c.1945C>T

Variant names:

• chr14-72974821-G-A
• rs757263132
• NM_021260.4:c.1945C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_021260.4(ZFYVE1):​c.1945C>T​(p.Arg649Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,459,676 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: ZFYVE1 NM_021260.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.66
• Publications: 0 publications found

Genes affected

ZFYVE1 (HGNC:13180): (zinc finger FYVE-type containing 1) The FYVE domain mediates the recruitment of proteins involved in membrane trafficking and cell signaling to phosphatidylinositol 3-phosphate-containing membranes. This protein contains two zinc-binding FYVE domains in tandem and is reported to localize to the Golgi apparatus. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2013]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.957

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021260.4. 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
	ZFYVE1	NM_021260.4	MANE Select	c.1945C>T	p.Arg649Trp	missense	Exon 10 of 12	NP_067083.1	Q9HBF4-1
	ZFYVE1	NM_001281734.2		c.1903C>T	p.Arg635Trp	missense	Exon 10 of 12	NP_001268663.1	Q9HBF4-3
	ZFYVE1	NM_001281735.1		c.700C>T	p.Arg234Trp	missense	Exon 7 of 9	NP_001268664.1	Q9HBF4-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZFYVE1	ENST00000556143.6	TSL:1 MANE Select	c.1945C>T	p.Arg649Trp	missense	Exon 10 of 12	ENSP00000450742.1	Q9HBF4-1
	ZFYVE1	ENST00000318876.9	TSL:1	c.1903C>T	p.Arg635Trp	missense	Exon 10 of 12	ENSP00000326921.5	Q9HBF4-3
	ZFYVE1	ENST00000555072.1	TSL:1	c.700C>T	p.Arg234Trp	missense	Exon 7 of 9	ENSP00000452232.1	Q9HBF4-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1459676 Hom.: 0 Cov.: 30 AF XY: 0.00000276 AC XY: 2 AN XY: 725734

African (AFR) AF: 0.00 AC: 0 AN: 33434

American (AMR) AF: 0.00 AC: 0 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39640

South Asian (SAS) AF: 0.00 AC: 0 AN: 86198

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5432

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1110496

Other (OTH) AF: 0.00 AC: 0 AN: 60280

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.42	T
Eigen	Pathogenic	0.80
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Pathogenic	4.8	H
PhyloP100		1.7
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-7.5	D
REVEL	Pathogenic	0.87
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.83		Loss of disorder (P = 0.0125)
MVP		0.85
MPC		2.3
ClinPred		1.0	D
GERP RS		4.2
Varity_R		0.63
gMVP		0.98
Mutation Taster		=42/58	disease causing

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: rs757263132; hg19: chr14-73441529; COSMIC: COSV100606549; COSMIC: COSV100606549;