3-88140191-T-G

Variant names:

• chr3-88140191-T-G
• rs7653652
• NM_001350134.2:c.2522T>G

Variant summary

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

The NM_001350134.2(ZNF654):​c.2522T>G​(p.Ile841Arg) 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 1,461,562 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.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ZNF654 NM_001350134.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.13
• Publications: 38 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=0.2715811).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF654	NM_001350134.2	MANE Select	c.2522T>G	p.Ile841Arg	missense	Exon 8 of 9	NP_001337063.1
	ZNF654	NM_001350135.2		c.2183T>G	p.Ile728Arg	missense	Exon 6 of 7	NP_001337064.1
	ZNF654	NM_001350136.2		c.1886T>G	p.Ile629Arg	missense	Exon 7 of 8	NP_001337065.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF654	ENST00000636215.2	TSL:5 MANE Select	c.2522T>G	p.Ile841Arg	missense	Exon 8 of 9	ENSP00000490842.1
	CGGBP1	ENST00000462901.5	TSL:1	c.-229+779A>C		intron	N/A	ENSP00000418769.1
	CGGBP1	ENST00000467332.1	TSL:4	c.-24+779A>C		intron	N/A	ENSP00000419459.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000402 AC: 1 AN: 248944 AF XY: 0.00000740

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461562 Hom.: 0 Cov.: 70 AF XY: 0.00000138 AC XY: 1 AN XY: 727054

African (AFR) AF: 0.00 AC: 0 AN: 33466

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: 39692

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111764

Other (OTH) AF: 0.00 AC: 0 AN: 60372

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	18
DANN	Benign	0.95
DEOGEN2	Benign	0.024	T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.28
FATHMM_MKL	Benign	0.44	N
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.0065	T
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		1.1
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.10
Sift	Benign	0.062	T
Sift4G	Benign	0.41	T
Polyphen		0.090	B
Vest4		0.27
MutPred		0.42		Gain of disorder (P = 0.003)
MVP		0.068
MPC		0.44
ClinPred		0.079	T
GERP RS		4.7
Varity_R		0.18
gMVP		0.33
Mutation Taster		=98/2	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: rs7653652; hg19: chr3-88189341;