Genetic Variant ZNF414:p.Met41Thr (chr19-8513223-A-G) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001146175.2(ZNF414):c.122T>C(p.Met41Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000171 in 1,581,374 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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. M41I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

ZNF414
NM_001146175.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.00

Variant links:

Genes affected

ZNF414 (HGNC:20630): (zinc finger protein 414) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to be located in nucleus. Predicted to be part of chromatin. [provided by Alliance of Genome Resources, Apr 2022]

ZNF414 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.035344213).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF414	NM_001146175.2 link	c.122T>C	p.Met41Thr	missense_variant	Exon 2 of 8	ENST00000393927.9	NP_001139647.1	Q96IQ9-2
ZNF414	NM_032370.3 link	c.122T>C	p.Met41Thr	missense_variant	Exon 2 of 6		NP_115746.2	Q96IQ9-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ZNF414	ENST00000393927.9 link	c.122T>C	p.Met41Thr	missense_variant	Exon 2 of 8	1	NM_001146175.2	ENSP00000377504.3	Q96IQ9-2
ZNF414	ENST00000255616.8 link	c.122T>C	p.Met41Thr	missense_variant	Exon 2 of 6	1		ENSP00000255616.7	Q96IQ9-1
ZNF414	ENST00000600906.1 link	n.240T>C		non_coding_transcript_exon_variant	Exon 2 of 2	2
ZNF414	ENST00000599379.1 link	n.4-512T>C		intron_variant	Intron 1 of 3	2		ENSP00000472741.1	M0R2Q9

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152096

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000293

AC:

AN:

204576

AF XY:

0.0000445

show subpopulations

Gnomad AFR exome

AF:

0.000495

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS 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:

0.0000119

AC:

AN:

1429278

Hom.:

Cov.:

AF XY:

0.0000113

AC XY:

AN XY:

709862

show subpopulations

African (AFR)

AF:

0.000393

AC:

AN:

33084

American (AMR)

AF:

0.00

AC:

AN:

41716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25636

East Asian (EAS)

AF:

0.00

AC:

AN:

38838

South Asian (SAS)

AF:

0.00

AC:

AN:

83408

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38722

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5718

European-Non Finnish (NFE)

AF:

0.00000272

AC:

AN:

1102652

Other (OTH)

AF:

0.0000168

AC:

AN:

59504

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000657

AC:

AN:

152096

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74308

show subpopulations

African (AFR)

AF:

0.000169

AC:

AN:

41418

American (AMR)

AF:

0.000131

AC:

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68018

Other (OTH)

AF:

0.00

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.000132

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000414

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 28, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.122T>C (p.M41T) alteration is located in exon 2 (coding exon 2) of the ZNF414 gene. This alteration results from a T to C substitution at nucleotide position 122, causing the methionine (M) at amino acid position 41 to be replaced by a threonine (T). 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

-0.44

BayesDel_noAF

Benign

-0.54

CADD

Benign

(source)

DANN

Benign

0.60

DEOGEN2

Benign

0.0048

.;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.23

LIST_S2

Benign

0.62

T;T

M_CAP

Benign

0.020

MetaRNN

Benign

0.035

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.69

N;N

PhyloP100

1.0

PrimateAI

Benign

0.48

PROVEAN

Benign

-1.0

N;N

REVEL

Benign

0.023

Sift

Uncertain

0.010

D;D

Sift4G

Benign

0.47

T;T

Polyphen

0.048

.;B

Vest4

0.26

MVP

0.13

MPC

0.30

ClinPred

0.028

GERP RS

1.7

Varity_R

0.11

gMVP

0.29

Mutation Taster

=94/6

polymorphism

(source)

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

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chr19-8513223-A-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over