Variant 19-11831546-A-G 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.370A>G(p.Asn124Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000205 in 1,461,818 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N124S) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

ZNF440
NM_152357.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.458

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=0.13249257).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
ZNF440	NM_152357.3 linkuse as main transcript	c.370A>G	p.Asn124Asp	missense_variant	4/4	ENST00000304060.10	NP_689570.2
ZNF440	XM_005259731.5 linkuse as main transcript	c.379A>G	p.Asn127Asp	missense_variant	4/4		XP_005259788.1
ZNF440	XM_047438145.1 linkuse as main transcript	c.376A>G	p.Asn126Asp	missense_variant	4/4		XP_047294101.1
ZNF440	XM_017026254.2 linkuse as main transcript	c.4A>G	p.Asn2Asp	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.370A>G	p.Asn124Asp	missense_variant	4/4	1	NM_152357.3	ENSP00000305373	P1
ZNF440	ENST00000427505.5 linkuse as main transcript	c.379A>G	p.Asn127Asp	missense_variant	4/4	3		ENSP00000393489
ZNF440	ENST00000414255.1 linkuse as main transcript	c.376A>G	p.Asn126Asp	missense_variant	3/3	2		ENSP00000411974
ZNF440	ENST00000457526.1 linkuse as main transcript	c.4A>G	p.Asn2Asp	missense_variant	3/3	4		ENSP00000404425

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000358

AC:

AN:

251394

Hom.:

AF XY:

0.0000442

AC XY:

AN XY:

135868

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000294

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000205

AC:

AN:

1461818

Hom.:

Cov.:

AF XY:

0.0000275

AC XY:

AN XY:

727210

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000267

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000480

Hom.:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

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

Dec 21, 2023

The c.370A>G (p.N124D) alteration is located in exon 4 (coding exon 4) of the ZNF440 gene. This alteration results from a A to G substitution at nucleotide position 370, causing the asparagine (N) at amino acid position 124 to be replaced by an aspartic acid (D). 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

0.15

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.77

CADD

Benign

4.9

DANN

Benign

0.96

DEOGEN2

Benign

0.043

T;.;.;.

Eigen

Benign

-0.87

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.0094

LIST_S2

Benign

0.068

T;T;T;T

M_CAP

Benign

0.00073

MetaRNN

Benign

0.13

T;T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.75

N;.;.;.

MutationTaster

Benign

1.0

PrimateAI

Benign

0.33

PROVEAN

Uncertain

-2.5

D;N;N;D

REVEL

Benign

0.042

Sift

Uncertain

0.0050

D;D;D;D

Sift4G

Uncertain

0.0030

D;T;D;D

Polyphen

0.75

P;.;.;.

Vest4

0.10

MutPred

0.54

Loss of loop (P = 0.2237);.;.;.;

MVP

0.28

MPC

0.10

ClinPred

0.20

GERP RS

-0.39

Varity_R

0.12

gMVP

0.017

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

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