Genetic Variant ZNF704:c.927+85A>C (chr8-80664730-T-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_001033723.3(ZNF704):c.927+85A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000391 in 1,536,194 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000036 ( 0 hom. )

Consequence

ZNF704
NM_001033723.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.68

Publications

5 publications found

Variant links:

Genes affected

ZNF704 (HGNC:32291): (zinc finger protein 704) Enables sequence-specific double-stranded 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]

ZNF704 links:

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ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.88).

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
ZNF704	NM_001033723.3 link	c.927+85A>C	intron_variant	Intron 6 of 8	ENST00000327835.7	NP_001028895.1
ZNF704	NM_001367783.1 link	c.1449+85A>C	intron_variant	Intron 6 of 8		NP_001354712.1
ZNF704	XM_017013725.2 link	c.951+85A>C	intron_variant	Intron 6 of 8		XP_016869214.1
ZNF704	XR_928797.3 link	n.1873+85A>C	intron_variant	Intron 6 of 9

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
ZNF704	ENST00000327835.7 link	c.927+85A>C	intron_variant	Intron 6 of 8	1	NM_001033723.3	ENSP00000331462.3
ZNF704	ENST00000519936.2 link	c.1449+85A>C	intron_variant	Intron 6 of 8	5		ENSP00000427715.2
ZNF704	ENST00000522040.5 link	n.*112A>C	downstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152132

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000361

AC:

AN:

1384062

Hom.:

AF XY:

0.00000437

AC XY:

AN XY:

687190

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:

31326

American (AMR)

AF:

0.00

AC:

AN:

41098

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23540

East Asian (EAS)

AF:

0.0000256

AC:

AN:

39076

South Asian (SAS)

AF:

0.0000251

AC:

AN:

79568

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52006

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5036

European-Non Finnish (NFE)

AF:

0.00000190

AC:

AN:

1055170

Other (OTH)

AF:

0.00

AC:

AN:

57242

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00153784), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.365

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152132

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74318

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41390

American (AMR)

AF:

0.00

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5204

South Asian (SAS)

AF:

0.000207

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68030

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

3889

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

0.035

(source)

DANN

Benign

0.50

PhyloP100

-2.7

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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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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