chr3-88140143-C-T

Variant names:

• chr3-88140143-C-T
• NM_001350134.2:c.2474C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001350134.2(ZNF654):​c.2474C>T​(p.Ser825Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ZNF654 NM_001350134.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.57
• Publications: 0 publications found

Genes affected

ZNF654 (HGNC:25612): (zinc finger protein 654) Predicted to enable DNA binding activity and DNA-binding transcription factor activity, RNA polymerase II-specific. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

CGGBP1 (HGNC:1888): (CGG triplet repeat binding protein 1) This gene encodes a CGG repeat-binding protein that primarily localizes to the nucleus. CGG trinucleotide repeats are implicated in many disorders as they often act as transcription- and translation-regulatory elements, can produce hairpin structures which cause DNA replication errors, and form regions prone to chromosomal breakage. CGG repeats are also targets for CpG methylation. In addition to its ability to bind CGG repeats and regulate transcription, this gene is believed to play a role in DNA damage repair and telomere protection. In vitro studies indicate this protein does not bind to methylated CpG sequences. [provided by RefSeq, Jul 2017]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.4123329).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001350134.2. 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
	ZNF654	NM_001350134.2	MANE Select	c.2474C>T	p.Ser825Leu	missense	Exon 8 of 9	NP_001337063.1	Q8IZM8
	ZNF654	NM_001350135.2		c.2135C>T	p.Ser712Leu	missense	Exon 6 of 7	NP_001337064.1
	ZNF654	NM_001350136.2		c.1838C>T	p.Ser613Leu	missense	Exon 7 of 8	NP_001337065.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF654	ENST00000636215.2	TSL:5 MANE Select	c.2474C>T	p.Ser825Leu	missense	Exon 8 of 9	ENSP00000490842.1	Q8IZM8
	CGGBP1	ENST00000462901.5	TSL:1	c.-229+827G>A		intron	N/A	ENSP00000418769.1	Q9UFW8
	ZNF654	ENST00000894932.1		c.2522C>T	p.Ser841Leu	missense	Exon 9 of 10	ENSP00000564991.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 51

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	0.34
BayesDel_addAF	Benign	-0.096	T
BayesDel_noAF	Benign	-0.38
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.41	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	0.34	N
PhyloP100		4.6
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-3.2	D
REVEL	Benign	0.17
Sift	Benign	0.063	T
Sift4G	Benign	0.070	T
Polyphen		0.97	D
Vest4		0.24
MutPred		0.46		Loss of ubiquitination at K280 (P = 0.0536)
MVP		0.068
MPC		0.28
ClinPred		0.86	D
GERP RS		5.0
Varity_R		0.17
gMVP		0.49
Mutation Taster		=89/11	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: chr3-88189293;