3-88140191-T-C

Position:

• chr3-88140191-T-C

Variant summary

Our verdict is Benign. Variant got -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. 13/20 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

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

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF654	NM_001350134.2	c.2522T>C	p.Ile841Thr	missense_variant	8/9	ENST00000636215.2	NP_001337063.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF654	ENST00000636215.2	c.2522T>C	p.Ile841Thr	missense_variant	8/9	5	NM_001350134.2	ENSP00000490842.1
CGGBP1	ENST00000462901.5	c.-229+779A>G		intron_variant		1		ENSP00000418769.1
CGGBP1	ENST00000467332.1	c.-24+779A>G		intron_variant		4		ENSP00000419459.1

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

GnomAD3 exomes AF: 0.845 AC: 210311 AN: 248944 Hom.: 89455 AF XY: 0.850 AC XY: 114783 AN XY: 135068

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 SAS exome AF: 0.909

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

Gnomad4 AFR exome AF: 0.603

Gnomad4 AMR exome AF: 0.866

Gnomad4 ASJ exome AF: 0.898

Gnomad4 EAS exome AF: 0.880

Gnomad4 SAS exome AF: 0.907

Gnomad4 FIN exome AF: 0.823

Gnomad4 NFE exome AF: 0.848

Gnomad4 OTH exome AF: 0.832

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

Gnomad4 AFR AF: 0.607

Gnomad4 AMR AF: 0.827

Gnomad4 ASJ AF: 0.903

Gnomad4 EAS AF: 0.845

Gnomad4 SAS AF: 0.909

Gnomad4 FIN AF: 0.822

Gnomad4 NFE AF: 0.854

Gnomad4 OTH AF: 0.805

Alfa AF: 0.845 Hom.: 102395

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 v4.3

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;T
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.78	T;T
MetaRNN	Benign	6.3e-7	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-0.69	.;N
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs7653652; hg19: chr3-88189341; COSMIC: COSV58805103; COSMIC: COSV58805103;