Genetic Variant ZNF414:p.Ala354_Ala366del (chr19-8510850-CCCGCGGGGGCGTCGGGGCGCGGCGGCCCGGCCGCGGGGG-C) – ACMG Classification: Benign (-7 pts)

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP3BP6_ModerateBS2

The NM_001146175.2(ZNF414):c.1061_1099delCCCCCGCGGCCGGGCCGCCGCGCCCCGACGCCCCCGCGG(p.Ala354_Ala366del) variant causes a disruptive inframe deletion, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00541 in 1,223,572 control chromosomes in the GnomAD database, including 134 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0027 ( 3 hom., cov: 31)

Exomes 𝑓: 0.0058 ( 131 hom. )

Consequence

ZNF414
NM_001146175.2 disruptive_inframe_deletion, splice_region

Scores

Not classified

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 2.20

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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_001146175.2

BP6

Variant 19-8510850-CCCGCGGGGGCGTCGGGGCGCGGCGGCCCGGCCGCGGGGG-C is Benign according to our data. Variant chr19-8510850-CCCGCGGGGGCGTCGGGGCGCGGCGGCCCGGCCGCGGGGG-C is described in ClinVar as [Likely_benign]. Clinvar id is 2649202.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF414	NM_001146175.2 link	c.1061_1099delCCCCCGCGGCCGGGCCGCCGCGCCCCGACGCCCCCGCGG	p.Ala354_Ala366del	disruptive_inframe_deletion, splice_region_variant	Exon 7 of 8	ENST00000393927.9	NP_001139647.1	Q96IQ9-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF414	ENST00000393927.9 link	c.1061_1099delCCCCCGCGGCCGGGCCGCCGCGCCCCGACGCCCCCGCGG	p.Ala354_Ala366del	disruptive_inframe_deletion, splice_region_variant	Exon 7 of 8	1	NM_001146175.2	ENSP00000377504.3		Q96IQ9-2

Frequencies

GnomAD3 genomes

AF:

0.00267

AC:

397

AN:

148958

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000755

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000401

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000194

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00926

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00400

Gnomad OTH

AF:

0.000974

GnomAD2 exomes

AF:

0.00871

AC:

294

AN:

33768

AF XY:

0.00788

show subpopulations

Gnomad AFR exome

AF:

0.00463

Gnomad AMR exome

AF:

0.00627

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00922

Gnomad FIN exome

AF:

0.0121

Gnomad NFE exome

AF:

0.0118

Gnomad OTH exome

AF:

0.00843

GnomAD4 exome

AF:

0.00579

AC:

6225

AN:

1074506

Hom.:

131

AF XY:

0.00576

AC XY:

2963

AN XY:

514130

show subpopulations

African (AFR)

AF:

0.000955

AC:

AN:

20940

American (AMR)

AF:

0.00243

AC:

AN:

9482

Ashkenazi Jewish (ASJ)

AF:

0.000371

AC:

AN:

13474

East Asian (EAS)

AF:

0.000527

AC:

AN:

20868

South Asian (SAS)

AF:

0.00203

AC:

AN:

34456

European-Finnish (FIN)

AF:

0.0101

AC:

323

AN:

31988

Middle Eastern (MID)

AF:

0.00456

AC:

AN:

3508

European-Non Finnish (NFE)

AF:

0.00623

AC:

5605

AN:

899086

Other (OTH)

AF:

0.00373

AC:

152

AN:

40704

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.590

Heterozygous variant carriers

364

728

1092

1456

1820

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00266

AC:

397

AN:

149066

Hom.:

Cov.:

AF XY:

0.00291

AC XY:

212

AN XY:

72772

show subpopulations

African (AFR)

AF:

0.000753

AC:

AN:

41172

American (AMR)

AF:

0.000400

AC:

AN:

14982

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3428

East Asian (EAS)

AF:

0.000195

AC:

AN:

5130

South Asian (SAS)

AF:

0.000622

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00926

AC:

AN:

9290

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.00400

AC:

268

AN:

66960

Other (OTH)

AF:

0.000963

AC:

AN:

2076

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.451

Heterozygous variant carriers

100

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00276

Hom.:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Dec 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ZNF414: BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.2

Mutation Taster

=160/40

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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19-8510850-CCCGCGGGGGCGTCGGGGCGCGGCGGCCCGGCCGCGGGGG-C

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