Genetic Variant ZNF414:p.Ala354_Ala366dup (chr19-8510850-C-CCCGCGGGGGCGTCGGGGCGCGGCGGCCCGGCCGCGGGGG) – ACMG Classification: Likely_benign (-1 pts)

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP3

The NM_001146175.2(ZNF414):c.1061_1099dupCCCCCGCGGCCGGGCCGCCGCGCCCCGACGCCCCCGCGG(p.Ala354_Ala366dup) variant causes a conservative inframe insertion, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000403 in 148,962 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000040 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000056 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ZNF414
NM_001146175.2 conservative_inframe_insertion, splice_region

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.15

Publications

1 publications found

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: Likely_benign. The variant received -1 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_001146175.2

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF414	NM_001146175.2 link	c.1061_1099dupCCCCCGCGGCCGGGCCGCCGCGCCCCGACGCCCCCGCGG	p.Ala354_Ala366dup	conservative_inframe_insertion, 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_1099dupCCCCCGCGGCCGGGCCGCCGCGCCCCGACGCCCCCGCGG	p.Ala354_Ala366dup	conservative_inframe_insertion, splice_region_variant	Exon 7 of 8	1	NM_001146175.2	ENSP00000377504.3		Q96IQ9-2

Frequencies

GnomAD3 genomes

AF:

0.0000403

AC:

AN:

148962

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000668

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000215

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000448

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000558

AC:

AN:

1074510

Hom.:

Cov.:

AF XY:

0.00000778

AC XY:

AN XY:

514130

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

20940

American (AMR)

AF:

0.00

AC:

AN:

9482

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

13474

East Asian (EAS)

AF:

0.00

AC:

AN:

20868

South Asian (SAS)

AF:

0.00

AC:

AN:

34456

European-Finnish (FIN)

AF:

0.00

AC:

AN:

31990

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3508

European-Non Finnish (NFE)

AF:

0.00000556

AC:

AN:

899088

Other (OTH)

AF:

0.0000246

AC:

AN:

40704

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.308

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000403

AC:

AN:

148962

Hom.:

Cov.:

AF XY:

0.0000275

AC XY:

AN XY:

72656

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41056

American (AMR)

AF:

0.0000668

AC:

AN:

14962

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3428

East Asian (EAS)

AF:

0.00

AC:

AN:

5146

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.000215

AC:

AN:

9292

Middle Eastern (MID)

AF:

0.00

AC:

AN:

312

European-Non Finnish (NFE)

AF:

0.0000448

AC:

AN:

66970

Other (OTH)

AF:

0.00

AC:

AN:

2054

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.2

Mutation Taster

=44/56

disease causing

(source)

Splicing

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

Publications

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chr19-8510850-C-CCCGCGGGGGCGTCGGGGCGCGGCGGCCCGGCCGCGGGGG

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over