1-52237553-C-G

Variant names:

• chr1-52237553-C-G
• rs151277176
• NM_004799.4:c.136C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004799.4(ZFYVE9):​c.136C>G​(p.Arg46Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,674 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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. R46W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ZFYVE9 NM_004799.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.22
• Publications: 0 publications found

Genes affected

ZFYVE9 (HGNC:6775): (zinc finger FYVE-type containing 9) This gene encodes a double zinc finger motif-containing protein that participates in the transforming growth factor-beta (TGFB) signalling pathway. The encoded protein interacts directly with SMAD2 and SMAD3, and recruits SMAD2 to the TGFB receptor. There are multiple pseudogenes for this gene on chromosomes 2, 15, and X. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2013]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11664501).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004799.4. 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
	ZFYVE9	NM_004799.4	MANE Select	c.136C>G	p.Arg46Gly	missense	Exon 4 of 19	NP_004790.2
	ZFYVE9	NM_007324.5		c.136C>G	p.Arg46Gly	missense	Exon 4 of 18	NP_015563.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZFYVE9	ENST00000287727.8	TSL:5 MANE Select	c.136C>G	p.Arg46Gly	missense	Exon 4 of 19	ENSP00000287727.3	O95405-1
	ZFYVE9	ENST00000371591.2	TSL:1	c.136C>G	p.Arg46Gly	missense	Exon 5 of 20	ENSP00000360647.1	O95405-1
	ZFYVE9	ENST00000357206.6	TSL:1	c.136C>G	p.Arg46Gly	missense	Exon 4 of 18	ENSP00000349737.2	O95405-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461674 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727134

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111856

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0077	T
Eigen	Benign	-0.10
Eigen_PC	Benign	0.0049
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.4	L
PhyloP100		2.2
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.085
Sift	Uncertain	0.0090	D
Sift4G	Benign	0.34	T
Polyphen		0.20	B
Vest4		0.17
MutPred		0.17		Loss of phosphorylation at S48 (P = 0.0835)
MVP		0.11
MPC		0.16
ClinPred		0.70	D
GERP RS		5.8
Varity_R		0.14
gMVP		0.28
Mutation Taster		=96/4	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: rs151277176; hg19: chr1-52703225;