NM_001284236.3:c.656A>T

Variant names:

• chr5-80437341-A-T
• rs141062809
• NM_001284236.3:c.656A>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001284236.3(ZFYVE16):​c.656A>T​(p.Tyr219Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000069 in 1,449,810 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y219C) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ZFYVE16 NM_001284236.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.967
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.056501836).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZFYVE16	NM_001284236.3	MANE Select	c.656A>T	p.Tyr219Phe	missense	Exon 4 of 19	NP_001271165.2	Q7Z3T8-1
	ZFYVE16	NM_001105251.4		c.656A>T	p.Tyr219Phe	missense	Exon 4 of 19	NP_001098721.2	Q7Z3T8-1
	ZFYVE16	NM_001349434.2		c.656A>T	p.Tyr219Phe	missense	Exon 4 of 19	NP_001336363.2	Q7Z3T8-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZFYVE16	ENST00000505560.5	TSL:1 MANE Select	c.656A>T	p.Tyr219Phe	missense	Exon 4 of 19	ENSP00000426848.1	Q7Z3T8-1
	ZFYVE16	ENST00000338008.9	TSL:1	c.656A>T	p.Tyr219Phe	missense	Exon 3 of 18	ENSP00000337159.5	Q7Z3T8-1
	ZFYVE16	ENST00000510158.5	TSL:1	c.656A>T	p.Tyr219Phe	missense	Exon 4 of 19	ENSP00000423663.1	Q7Z3T8-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.90e-7 AC: 1 AN: 1449810 Hom.: 0 Cov.: 66 AF XY: 0.00 AC XY: 0 AN XY: 721048

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32584

American (AMR) AF: 0.00 AC: 0 AN: 41068

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25376

East Asian (EAS) AF: 0.00 AC: 0 AN: 39614

South Asian (SAS) AF: 0.00 AC: 0 AN: 84684

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53062

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5676

European-Non Finnish (NFE) AF: 9.03e-7 AC: 1 AN: 1107988

Other (OTH) AF: 0.00 AC: 0 AN: 59758

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	9.7
DANN	Benign	0.35
DEOGEN2	Benign	0.0016	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.58	T
M_CAP	Benign	0.0040	T
MetaRNN	Benign	0.057	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N
PhyloP100		0.97
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.26	N
REVEL	Benign	0.033
Sift	Uncertain	0.012	D
Sift4G	Benign	0.73	T
Polyphen		0.022	B
Vest4		0.13
MutPred		0.54		Loss of phosphorylation at Y219 (P = 0.0577)
MVP		0.34
MPC		0.043
ClinPred		0.083	T
GERP RS		1.4
Varity_R		0.071
gMVP		0.064
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs141062809; hg19: chr5-79733160;