19-23744076-T-C

Position:

• chr19-23744076-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_138286.3(ZNF681):​c.1474A>G​(p.Ile492Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 34)
• Consequence: ZNF681 NM_138286.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -6.81

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.066496104).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF681	NM_138286.3	c.1474A>G	p.Ile492Val	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.1474A>G	p.Ile492Val	missense_variant	4/4	1	NM_138286.3	ENSP00000384000.3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 89

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

Dec 08, 2023

The c.1474A>G (p.I492V) alteration is located in exon 4 (coding exon 4) of the ZNF681 gene. This alteration results from a A to G substitution at nucleotide position 1474, causing the isoleucine (I) at amino acid position 492 to be replaced by a valine (V). 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	Benign	0.11
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.13
DANN	Benign	0.44
DEOGEN2	Benign	0.00076	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.0019	N
LIST_S2	Benign	0.022	T
M_CAP	Benign	0.0017	T
MetaRNN	Benign	0.066	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-0.14	N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.37	N
REVEL	Benign	0.11
Sift	Benign	0.58	T
Sift4G	Benign	0.50	T
Polyphen		0.33	B
Vest4		0.059
MutPred		0.21		Loss of stability (P = 0.0821);
MVP		0.014
MPC		0.0075
ClinPred		0.071	T
GERP RS		-3.0
Varity_R		0.022
gMVP		0.0047

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: chr19-23926878;