rs61741923

Variant names:

• chr5-80473857-G-A
• rs61741923
• NM_001284236.3:c.4291G>A

Your query was ambiguous. Multiple possible variants found:

• chr5-80473857-G-A
• chr5-80473857-G-C
• chr5-80473857-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001284236.3(ZFYVE16):​c.4291G>A​(p.Glu1431Lys) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000013 in 1,609,852 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: ZFYVE16 NM_001284236.3 missense, splice_region
• Scores: Splicing: ADA: 0.9498
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.46
• Publications: 2 publications found

Genes affected

ZFYVE16 (HGNC:20756): (zinc finger FYVE-type containing 16) This gene encodes an endosomal protein that belongs to the FYVE zinc finger family of proteins. The encoded protein is thought to regulate membrane trafficking in the endosome. This protein functions as a scaffold protein in the transforming growth factor-beta signaling pathway and is involved in positive and negative feedback regulation of the bone morphogenetic protein signaling pathway. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Sep 2013]

FAM151B-DT (HGNC:55578): (FAM151B divergent transcript)

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.807

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001284236.3. 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
	ZFYVE16	NM_001284236.3	MANE Select	c.4291G>A	p.Glu1431Lys	missense splice_region	Exon 17 of 19	NP_001271165.2
	ZFYVE16	NM_001105251.4		c.4291G>A	p.Glu1431Lys	missense splice_region	Exon 17 of 19	NP_001098721.2
	ZFYVE16	NM_001349434.2		c.4291G>A	p.Glu1431Lys	missense splice_region	Exon 17 of 19	NP_001336363.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZFYVE16	ENST00000505560.5	TSL:1 MANE Select	c.4291G>A	p.Glu1431Lys	missense splice_region	Exon 17 of 19	ENSP00000426848.1
	ZFYVE16	ENST00000338008.9	TSL:1	c.4291G>A	p.Glu1431Lys	missense splice_region	Exon 16 of 18	ENSP00000337159.5
	ZFYVE16	ENST00000510158.5	TSL:1	c.4291G>A	p.Glu1431Lys	missense splice_region	Exon 17 of 19	ENSP00000423663.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152184 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000201 AC: 5 AN: 248840 AF XY: 0.0000149

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000883

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000886

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000123 AC: 18 AN: 1457668 Hom.: 0 Cov.: 28 AF XY: 0.0000124 AC XY: 9 AN XY: 725098

African (AFR) AF: 0.00 AC: 0 AN: 33332

American (AMR) AF: 0.000158 AC: 7 AN: 44286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26032

East Asian (EAS) AF: 0.00 AC: 0 AN: 39536

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85574

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53334

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5746

European-Non Finnish (NFE) AF: 0.00000811 AC: 9 AN: 1109592

Other (OTH) AF: 0.0000166 AC: 1 AN: 60236

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152184 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74348

African (AFR) AF: 0.00 AC: 0 AN: 41438

American (AMR) AF: 0.0000655 AC: 1 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.0000247 AC: 3

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Uncertain	0.084	D
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.20	T
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.035	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Benign	-0.48	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		5.5
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-3.9	D
REVEL	Uncertain	0.40
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.82
MutPred		0.58		Gain of methylation at E1431 (P = 0.0145)
MVP		0.76
MPC		0.080
ClinPred		0.78	D
GERP RS		6.0
Varity_R		0.46
gMVP		0.44
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.95
dbscSNV1_RF	Pathogenic	0.83
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

Other links and lift over

dbSNP: rs61741923; hg19: chr5-79769676; COSMIC: COSV62014341;