chr19-23744387-T-A

Position:

• chr19-23744387-T-A

Variant summary

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

The ENST00000402377.3(ZNF681):​c.1163A>T​(p.His388Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 34)
• Consequence: ZNF681 ENST00000402377.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.11

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.1163A>T	p.His388Leu	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.1163A>T	p.His388Leu	missense_variant	4/4	1	NM_138286.3	ENSP00000384000	P1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 90

GnomAD4 genome Cov.: 34

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

Aug 20, 2023

The c.1163A>T (p.H388L) alteration is located in exon 4 (coding exon 4) of the ZNF681 gene. This alteration results from a A to T substitution at nucleotide position 1163, causing the histidine (H) at amino acid position 388 to be replaced by a leucine (L). 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	Uncertain	0.52
BayesDel_addAF	Uncertain	0.045	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	19
DANN	Benign	0.95
DEOGEN2	Benign	0.21	T
Eigen	Uncertain	0.22
Eigen_PC	Benign	-0.075
FATHMM_MKL	Benign	0.45	N
LIST_S2	Benign	0.14	T
M_CAP	Benign	0.0020	T
MetaRNN	Uncertain	0.71	D
MetaSVM	Uncertain	0.054	D
MutationAssessor	Pathogenic	4.0	H
MutationTaster	Benign	0.87	D;D
PrimateAI	Uncertain	0.52	T
PROVEAN	Pathogenic	-10	D
REVEL	Benign	0.26
Sift	Uncertain	0.013	D
Sift4G	Uncertain	0.0070	D
Polyphen		1.0	D
Vest4		0.24
MutPred		0.76		Loss of ubiquitination at K392 (P = 0.039);
MVP		0.41
MPC		0.012
ClinPred		0.81	D
GERP RS		1.5
Varity_R		0.38
gMVP		0.030

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-23927189;