Genetic Variant ZNF44:p.Met384Ile (chr19-12273103-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

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

The NM_016264.4(ZNF44):c.1152G>A(p.Met384Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,613,734 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 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. M384V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

ZNF44
NM_016264.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.725

Variant links:

Genes affected

ZNF44 (HGNC:13110): (zinc finger protein 44) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II transcription 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]

ZNF44 links:

Genome browser will be placed here

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=0.07433453).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF44	NM_016264.4 link	c.1152G>A	p.Met384Ile	missense_variant	Exon 4 of 4	ENST00000355684.6	NP_057348.3	F8W7T7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF44	ENST00000355684.6 link	c.1152G>A	p.Met384Ile	missense_variant	Exon 4 of 4	2	NM_016264.4	ENSP00000347910.5		F8W7T7

Frequencies

GnomAD3 genomes

AF:

0.0000921

AC:

AN:

152010

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000314

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:

0.000479

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

251264

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135884

show subpopulations

Gnomad AFR exome

AF:

0.000309

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461724

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727134

show subpopulations

Gnomad4 AFR exome

AF:

0.000119

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000921

AC:

AN:

152010

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74252

show subpopulations

Gnomad4 AFR

AF:

0.000314

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:

0.000479

Alfa

AF:

0.0000658

Hom.:

Bravo

AF:

0.0000945

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 01, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1296G>A (p.M432I) alteration is located in exon 5 (coding exon 5) of the ZNF44 gene. This alteration results from a G to A substitution at nucleotide position 1296, causing the methionine (M) at amino acid position 432 to be replaced by an isoleucine (I). 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

Uncertain

0.44

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.64

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.0063

T;.

Eigen

Benign

-0.62

Eigen_PC

Benign

-0.86

FATHMM_MKL

Benign

0.000010

LIST_S2

Benign

0.16

T;T

M_CAP

Benign

0.0010

MetaRNN

Benign

0.074

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.2

L;.

PrimateAI

Benign

0.31

PROVEAN

Benign

-1.8

N;N

REVEL

Benign

0.067

Sift

Benign

0.046

D;D

Sift4G

Uncertain

0.014

D;D

Polyphen

0.98

D;D

Vest4

0.18

MutPred

0.36

Loss of disorder (P = 0.0779);.;

MVP

0.29

MPC

0.38

ClinPred

0.33

GERP RS

-1.8

Varity_R

0.17

gMVP

0.029

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