4-442201-T-C

Position:

• chr4-442201-T-C

Variant summary

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

The NM_133474.4(ZNF721):​c.2266A>G​(p.Lys756Glu) 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: 33)
• Consequence: ZNF721 NM_133474.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.76

Genes affected

ZNF721 (HGNC:29425): (zinc finger protein 721) Predicted to enable DNA-binding transcription activator 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]

ABCA11P (HGNC:):

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=0.03685391).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF721	NM_133474.4	c.2266A>G	p.Lys756Glu	missense_variant	3/3	ENST00000511833.3	NP_597731.2
ABCA11P	NR_002451.2	n.357-15228A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF721	ENST00000511833.3	c.2266A>G	p.Lys756Glu	missense_variant	3/3	4	NM_133474.4	ENSP00000428878.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

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

Sep 27, 2021

The c.2266A>G (p.K756E) alteration is located in exon 3 (coding exon 2) of the ZNF721 gene. This alteration results from a A to G substitution at nucleotide position 2266, causing the lysine (K) at amino acid position 756 to be replaced by a glutamic acid (E). 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	0.084
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	0.41
DANN	Benign	0.42
DEOGEN2	Benign	0.00045	T;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0	N
LIST_S2	Benign	0.0089	T;T
M_CAP	Benign	0.00065	T
MetaRNN	Benign	0.037	T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.71	N;.
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.73	N;N
REVEL	Benign	0.0060
Sift	Benign	0.78	T;T
Sift4G	Benign	0.42	T;T
Polyphen		0.051	B;B
Vest4		0.16
MutPred		0.37		Loss of methylation at K744 (P = 3e-04);.;
MVP		0.10
MPC		0.016
ClinPred		0.024	T
GERP RS		-2.6
Varity_R		0.031
gMVP		0.022

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: chr4-435990;