19-11830346-A-G

Position:

• chr19-11830346-A-G

Variant summary

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

The NM_152357.3(ZNF440):​c.67A>G​(p.Ile23Val) 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: 32)
• Consequence: ZNF440 NM_152357.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.949

Genes affected

ZNF440 (HGNC:20874): (zinc finger protein 440) Predicted to enable DNA-binding transcription repressor activity, RNA polymerase II-specific and RNA polymerase II transcription regulatory region sequence-specific DNA binding activity. Predicted to be involved in negative regulation of transcription by RNA polymerase II. Predicted to be located in nucleus. [provided by Alliance of Genome Resources, Apr 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=0.061023295).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF440	NM_152357.3	c.67A>G	p.Ile23Val	missense_variant	2/4	ENST00000304060.10	NP_689570.2
ZNF440	XM_005259731.5	c.76A>G	p.Ile26Val	missense_variant	2/4		XP_005259788.1
ZNF440	XM_047438145.1	c.73A>G	p.Ile25Val	missense_variant	2/4		XP_047294101.1
ZNF440	XM_017026254.2	c.-236-271A>G		intron_variant			XP_016881743.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF440	ENST00000304060.10	c.67A>G	p.Ile23Val	missense_variant	2/4	1	NM_152357.3	ENSP00000305373.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

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 27, 2022

The c.67A>G (p.I23V) alteration is located in exon 2 (coding exon 2) of the ZNF440 gene. This alteration results from a A to G substitution at nucleotide position 67, causing the isoleucine (I) at amino acid position 23 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	-0.28	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	7.6
DANN	Benign	0.51
DEOGEN2	Benign	0.0018	T;.;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0059	N
LIST_S2	Benign	0.12	T;T;T
M_CAP	Benign	0.00085	T
MetaRNN	Benign	0.061	T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-0.69	N;.;.
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.47	N;N;N
REVEL	Benign	0.054
Sift	Uncertain	0.011	D;D;D
Sift4G	Uncertain	0.0060	D;D;D
Polyphen		0.88	P;.;.
Vest4		0.10
MutPred		0.43		Loss of catalytic residue at L28 (P = 0.0561);.;.;
MVP		0.076
MPC		0.20
ClinPred		0.34	T
GERP RS		-3.5
Varity_R		0.079
gMVP		0.020

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr19-11941161;