Variant 19-11831553-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_152357.3(ZNF440):c.377G>A(p.Arg126Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000197 in 152,146 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Consequence

ZNF440
NM_152357.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -3.54

Variant links:

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]

ZNF440 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.1083594).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
ZNF440	NM_152357.3 linkuse as main transcript	c.377G>A	p.Arg126Lys	missense_variant	4/4	ENST00000304060.10	NP_689570.2
ZNF440	XM_005259731.5 linkuse as main transcript	c.386G>A	p.Arg129Lys	missense_variant	4/4		XP_005259788.1
ZNF440	XM_047438145.1 linkuse as main transcript	c.383G>A	p.Arg128Lys	missense_variant	4/4		XP_047294101.1
ZNF440	XM_017026254.2 linkuse as main transcript	c.11G>A	p.Arg4Lys	missense_variant	3/3		XP_016881743.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
ZNF440	ENST00000304060.10 linkuse as main transcript	c.377G>A	p.Arg126Lys	missense_variant	4/4	1	NM_152357.3	ENSP00000305373	P1
ZNF440	ENST00000427505.5 linkuse as main transcript	c.386G>A	p.Arg129Lys	missense_variant	4/4	3		ENSP00000393489
ZNF440	ENST00000414255.1 linkuse as main transcript	c.383G>A	p.Arg128Lys	missense_variant	3/3	2		ENSP00000411974
ZNF440	ENST00000457526.1 linkuse as main transcript	c.11G>A	p.Arg4Lys	missense_variant	3/3	4		ENSP00000404425

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152146

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74326

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 13, 2021

The c.377G>A (p.R126K) alteration is located in exon 4 (coding exon 4) of the ZNF440 gene. This alteration results from a G to A substitution at nucleotide position 377, causing the arginine (R) at amino acid position 126 to be replaced by a lysine (K). 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

0.13

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.69

CADD

Benign

0.67

DANN

Benign

0.83

DEOGEN2

Benign

0.039

T;.;.;.

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.000020

LIST_S2

Benign

0.28

T;T;T;T

M_CAP

Benign

0.00055

MetaRNN

Benign

0.11

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.9

L;.;.;.

MutationTaster

Benign

1.0

PrimateAI

Benign

0.24

PROVEAN

Uncertain

-2.4

N;D;N;D

REVEL

Benign

0.0090

Sift

Benign

0.085

T;D;T;T

Sift4G

Benign

0.077

T;D;T;T

Polyphen

0.33

B;.;.;.

Vest4

0.036

MutPred

0.46

Gain of ubiquitination at R126 (P = 0.0155);.;.;.;

MVP

0.28

MPC

0.044

ClinPred

0.14

GERP RS

-1.8

Varity_R

0.090

gMVP

0.027

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over