3-88140191-T-C

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001350134.2(ZNF654):​c.2522T>C​(p.Ile841Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.841 in 1,613,602 control chromosomes in the GnomAD database, including 573,055 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 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: 𝑓 0.78 (47588 hom., cov: 32)
  • Exomes 𝑓: 0.85 (525467 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=6.3256596E-7).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.887 is higher than 0.05.

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.2522T>C	p.Ile841Thr	missense	Exon 8 of 9	NP_001337063.1	Q8IZM8
	ZNF654	NM_001350135.2		c.2183T>C	p.Ile728Thr	missense	Exon 6 of 7	NP_001337064.1
	ZNF654	NM_001350136.2		c.1886T>C	p.Ile629Thr	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.2522T>C	p.Ile841Thr	missense	Exon 8 of 9	ENSP00000490842.1	Q8IZM8
	CGGBP1	ENST00000462901.5	TSL:1	c.-229+779A>G		intron	N/A	ENSP00000418769.1	Q9UFW8
	ZNF654	ENST00000894932.1		c.2570T>C	p.Ile857Thr	missense	Exon 9 of 10	ENSP00000564991.1

Frequencies

GnomAD3 genomes AF: 0.783 AC: 119014 AN: 151936 Hom.: 47535 Cov.: 32

Gnomad AFR AF: 0.606

Gnomad AMI AF: 0.833

Gnomad AMR AF: 0.827

Gnomad ASJ AF: 0.903

Gnomad EAS AF: 0.845

Gnomad SAS AF: 0.910

Gnomad FIN AF: 0.822

Gnomad MID AF: 0.845

Gnomad NFE AF: 0.854

Gnomad OTH AF: 0.803

GnomAD2 exomes AF: 0.845 AC: 210311 AN: 248944 AF XY: 0.850

Gnomad AFR exome AF: 0.602

Gnomad AMR exome AF: 0.869

Gnomad ASJ exome AF: 0.901

Gnomad EAS exome AF: 0.844

Gnomad FIN exome AF: 0.822

Gnomad NFE exome AF: 0.852

Gnomad OTH exome AF: 0.851

GnomAD4 exome AF: 0.847 AC: 1237314 AN: 1461548 Hom.: 525467 Cov.: 70 AF XY: 0.850 AC XY: 617889 AN XY: 727050

African (AFR) AF: 0.603 AC: 20174 AN: 33466

American (AMR) AF: 0.866 AC: 38716 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.898 AC: 23471 AN: 26130

East Asian (EAS) AF: 0.880 AC: 34948 AN: 39692

South Asian (SAS) AF: 0.907 AC: 78211 AN: 86254

European-Finnish (FIN) AF: 0.823 AC: 43974 AN: 53400

Middle Eastern (MID) AF: 0.857 AC: 4941 AN: 5768

European-Non Finnish (NFE) AF: 0.848 AC: 942622 AN: 1111756

Other (OTH) AF: 0.832 AC: 50257 AN: 60372

GnomAD4 genome AF: 0.783 AC: 119127 AN: 152054 Hom.: 47588 Cov.: 32 AF XY: 0.785 AC XY: 58388 AN XY: 74354

African (AFR) AF: 0.607 AC: 25135 AN: 41438

American (AMR) AF: 0.827 AC: 12620 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.903 AC: 3135 AN: 3470

East Asian (EAS) AF: 0.845 AC: 4375 AN: 5178

South Asian (SAS) AF: 0.909 AC: 4385 AN: 4822

European-Finnish (FIN) AF: 0.822 AC: 8708 AN: 10594

Middle Eastern (MID) AF: 0.864 AC: 254 AN: 294

European-Non Finnish (NFE) AF: 0.854 AC: 58055 AN: 67974

Other (OTH) AF: 0.805 AC: 1700 AN: 2112

Alfa AF: 0.835 Hom.: 133437

Bravo AF: 0.774

TwinsUK AF: 0.854 AC: 3166

ALSPAC AF: 0.849 AC: 3272

ESP6500AA AF: 0.637 AC: 2396

ESP6500EA AF: 0.855 AC: 7034

ExAC AF: 0.842 AC: 101759

EpiCase AF: 0.853

EpiControl AF: 0.852

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	17
DANN	Benign	0.80
DEOGEN2	Benign	0.0092	T
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.78	T
MetaRNN	Benign	6.3e-7	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-0.69	N
PhyloP100		1.1
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.98	N
REVEL	Benign	0.067
Sift	Benign	0.34	T
Sift4G	Benign	0.69	T
Polyphen		0.039	B
Vest4		0.072
MPC		0.27
ClinPred		0.0047	T
GERP RS		4.7
Varity_R		0.055
gMVP		0.25
Mutation Taster		=98/2	polymorphism (auto)

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; COSMIC: COSV58805103; COSMIC: COSV58805103;