chr1-52237650-C-T

Variant names:

• chr1-52237650-C-T
• NM_004799.4:c.233C>T

Variant summary

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

The NM_004799.4(ZFYVE9):​c.233C>T​(p.Ala78Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,788 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ZFYVE9 NM_004799.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.69
• 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: 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=0.036988854).

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.233C>T	p.Ala78Val	missense	Exon 4 of 19	NP_004790.2
	ZFYVE9	NM_007324.5		c.233C>T	p.Ala78Val	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.233C>T	p.Ala78Val	missense	Exon 4 of 19	ENSP00000287727.3	O95405-1
	ZFYVE9	ENST00000371591.2	TSL:1	c.233C>T	p.Ala78Val	missense	Exon 5 of 20	ENSP00000360647.1	O95405-1
	ZFYVE9	ENST00000357206.6	TSL:1	c.233C>T	p.Ala78Val	missense	Exon 4 of 18	ENSP00000349737.2	O95405-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461788 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727196

African (AFR) AF: 0.00 AC: 0 AN: 33474

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111950

Other (OTH) AF: 0.00 AC: 0 AN: 60386

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	Benign	0.070
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	6.2
DANN	Benign	0.58
DEOGEN2	Benign	0.0019	T
Eigen	Benign	-0.98
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.0043	T
MetaRNN	Benign	0.037	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.20	N
PhyloP100		1.7
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.14	N
REVEL	Benign	0.080
Sift	Benign	0.34	T
Sift4G	Benign	0.54	T
Polyphen		0.0	B
Vest4		0.060
MutPred		0.16		Loss of disorder (P = 0.0731)
MVP		0.043
MPC		0.10
ClinPred		0.058	T
GERP RS		2.6
Varity_R		0.032
gMVP		0.084
Mutation Taster		=100/0	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

hg19: chr1-52703322; COSMIC: COSV99053858;