chr14-72998319-C-A

Position:

• chr14-72998319-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_021260.4(ZFYVE1):​c.484-4G>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00774 in 1,220,556 control chromosomes in the GnomAD database, including 116 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0022 (0 hom., cov: 19)
  • Exomes 𝑓: 0.0084 (116 hom.)
• Consequence: ZFYVE1 NM_021260.4 splice_region, intron
• Scores: Splicing: ADA: 0.00001594
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.589

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

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 14-72998319-C-A is Benign according to our data. Variant chr14-72998319-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 769864.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.0084 (9161/1091020) while in subpopulation SAS AF= 0.0442 (1566/35416). AF 95% confidence interval is 0.0424. There are 116 homozygotes in gnomad4_exome. There are 5070 alleles in male gnomad4_exome subpopulation. Median coverage is 22. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 289 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZFYVE1	NM_021260.4	c.484-4G>T		splice_region_variant, intron_variant		ENST00000556143.6	NP_067083.1
ZFYVE1	NM_001281734.2	c.484-4G>T		splice_region_variant, intron_variant			NP_001268663.1
ZFYVE1	XM_047431481.1	c.484-4G>T		splice_region_variant, intron_variant			XP_047287437.1
ZFYVE1	XM_047431482.1	c.-765-1G>T		splice_acceptor_variant, intron_variant			XP_047287438.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZFYVE1	ENST00000556143.6	c.484-4G>T		splice_region_variant, intron_variant		1	NM_021260.4	ENSP00000450742.1
ZFYVE1	ENST00000318876.9	c.484-4G>T		splice_region_variant, intron_variant		1		ENSP00000326921.5
ZFYVE1	ENST00000553891.5	c.484-4G>T		splice_region_variant, intron_variant		5		ENSP00000452442.1

Frequencies

GnomAD3 genomes AF: 0.00223 AC: 289 AN: 129534 Hom.: 0 Cov.: 19

Gnomad AFR AF: 0.00183

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00191

Gnomad ASJ AF: 0.00123

Gnomad EAS AF: 0.000900

Gnomad SAS AF: 0.000977

Gnomad FIN AF: 0.00476

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00248

Gnomad OTH AF: 0.00283

GnomAD3 exomes AF: 0.0169 AC: 1253 AN: 74120 Hom.: 21 AF XY: 0.0168 AC XY: 685 AN XY: 40712

Gnomad AFR exome AF: 0.0133

Gnomad AMR exome AF: 0.0228

Gnomad ASJ exome AF: 0.0283

Gnomad EAS exome AF: 0.0288

Gnomad SAS exome AF: 0.0289

Gnomad FIN exome AF: 0.0124

Gnomad NFE exome AF: 0.0119

Gnomad OTH exome AF: 0.0268

GnomAD4 exome AF: 0.00840 AC: 9161 AN: 1091020 Hom.: 116 Cov.: 22 AF XY: 0.00962 AC XY: 5070 AN XY: 527250

Gnomad4 AFR exome AF: 0.00779

Gnomad4 AMR exome AF: 0.0303

Gnomad4 ASJ exome AF: 0.0118

Gnomad4 EAS exome AF: 0.0152

Gnomad4 SAS exome AF: 0.0442

Gnomad4 FIN exome AF: 0.0182

Gnomad4 NFE exome AF: 0.00585

Gnomad4 OTH exome AF: 0.00875

GnomAD4 genome AF: 0.00223 AC: 289 AN: 129536 Hom.: 0 Cov.: 19 AF XY: 0.00224 AC XY: 139 AN XY: 61966

Gnomad4 AFR AF: 0.00183

Gnomad4 AMR AF: 0.00190

Gnomad4 ASJ AF: 0.00123

Gnomad4 EAS AF: 0.000903

Gnomad4 SAS AF: 0.000982

Gnomad4 FIN AF: 0.00476

Gnomad4 NFE AF: 0.00248

Gnomad4 OTH AF: 0.00281

Alfa AF: 0.00111 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 07, 2018	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.69
DANN	Benign	0.43

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000016
dbscSNV1_RF	Benign	0.0
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

Publications

LitVar

Other links and lift over

dbSNP: rs868547445; hg19: chr14-73465027;