8-143651061-C-G

Position:

• chr8-143651061-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001261843.2(ZNF623):​c.1069C>G​(p.His357Asp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ZNF623 NM_001261843.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.93

Genes affected

ZNF623 (HGNC:29084): (zinc finger protein 623) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. 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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.943

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNF623	NM_001261843.2	c.1069C>G	p.His357Asp	missense_variant	2/2	ENST00000526926.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNF623	ENST00000526926.6	c.1069C>G	p.His357Asp	missense_variant	2/2	2	NM_001261843.2	P2
ZNF623	ENST00000458270.2	c.1069C>G	p.His357Asp	missense_variant	2/2	1		P2
ZNF623	ENST00000501748.3	c.1189C>G	p.His397Asp	missense_variant	1/1			A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 04, 2024

The c.1189C>G (p.H397D) alteration is located in exon 1 (coding exon 1) of the ZNF623 gene. This alteration results from a C to G substitution at nucleotide position 1189, causing the histidine (H) at amino acid position 397 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Benign	0.38	.;.;T
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Benign	0.50	N
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.94	D;D;D
MetaSVM	Uncertain	0.59	D
MutationTaster	Benign	0.59	D;D;D;D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-9.0	D;D;D
REVEL	Uncertain	0.48
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Vest4		0.66
MutPred		0.80		.;.;Loss of methylation at K395 (P = 0.066);
MVP		0.90
MPC		1.1
ClinPred		1.0	D
GERP RS		4.0
gMVP		0.35

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1815298223; hg19: chr8-144733231;