19-23743726-A-T

Position:

• chr19-23743726-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The ENST00000402377.3(ZNF681):​c.1824T>A​(p.His608Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ZNF681 ENST00000402377.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0780

Genes affected

ZNF681 (HGNC:26457): (zinc finger protein 681) This gene encodes a protein containing the krueppel associated box (KRAB) and zinc-finger domains, which may be involved in transcriptional regulation. Non-functional alleles of this gene are present in alternate genome assemblies including T2T-CHM13v1.1, resulting from a 'TG' deletion (rs61397759) which causes a frameshift and a premature stop codon. [provided by RefSeq, Sep 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF681	NM_138286.3	c.1824T>A	p.His608Gln	missense_variant	4/4	ENST00000402377.3	NP_612143.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF681	ENST00000402377.3	c.1824T>A	p.His608Gln	missense_variant	4/4	1	NM_138286.3	ENSP00000384000	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

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

Dec 11, 2023

The c.1824T>A (p.H608Q) alteration is located in exon 4 (coding exon 4) of the ZNF681 gene. This alteration results from a T to A substitution at nucleotide position 1824, causing the histidine (H) at amino acid position 608 to be replaced by a glutamine (Q). 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	0.81
BayesDel_addAF	Benign	-0.019	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	16
DANN	Benign	0.94
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.029	N
LIST_S2	Benign	0.22	T
M_CAP	Benign	0.0049	T
MetaRNN	Uncertain	0.48	T
MetaSVM	Benign	-0.50	T
MutationAssessor	Pathogenic	3.6	H
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-5.3	D
REVEL	Benign	0.26
Sift	Uncertain	0.027	D
Sift4G	Uncertain	0.015	D
Polyphen		0.81	P
Vest4		0.27
MutPred		0.77		Loss of catalytic residue at K609 (P = 0.0691);
MVP		0.14
MPC		0.015
ClinPred		0.43	T
GERP RS		0.34
Varity_R		0.24
gMVP		0.040

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-23926528;