Genetic Variant YY1:p.Lys179Gln (chr14-100239779-A-C) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The NM_003403.5(YY1):c.535A>C(p.Lys179Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000142 in 1,410,032 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 30)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

YY1
NM_003403.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.42

Publications

0 publications found

Variant links:

Genes affected

YY1 (HGNC:12856): (YY1 transcription factor) YY1 is a ubiquitously distributed transcription factor belonging to the GLI-Kruppel class of zinc finger proteins. The protein is involved in repressing and activating a diverse number of promoters. YY1 may direct histone deacetylases and histone acetyltransferases to a promoter in order to activate or repress the promoter, thus implicating histone modification in the function of YY1. [provided by RefSeq, Jul 2008]

YY1 Gene-Disease associations (from GenCC):

Gabriele de Vries syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)

YY1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the YY1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 20 curated pathogenic missense variants (we use a threshold of 10). The gene has 3 curated benign missense variants. Gene score misZ: 3.3086 (above the threshold of 3.09). Trascript score misZ: 3.5888 (above the threshold of 3.09). GenCC associations: The gene is linked to Gabriele de Vries syndrome.

BP4

Computational evidence support a benign effect (MetaRNN=0.20171323).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
YY1	NM_003403.5 link	c.535A>C	p.Lys179Gln	missense_variant	Exon 1 of 5	ENST00000262238.10	NP_003394.1	P25490

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
YY1	ENST00000262238.10 link	c.535A>C	p.Lys179Gln	missense_variant	Exon 1 of 5	1	NM_003403.5	ENSP00000262238.4	P25490
YY1	ENST00000554804.1 link	c.19A>C	p.Lys7Gln	missense_variant	Exon 1 of 4	3		ENSP00000452225.1	H0YJV7
YY1	ENST00000553625.5 link	c.25A>C	p.Lys9Gln	missense_variant	Exon 1 of 3	2		ENSP00000452140.1	H0YJU4
YY1	ENST00000651219.1 link	n.-108A>C		upstream_gene_variant				ENSP00000498329.1	A0A494C032

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000142

AC:

AN:

1410032

Hom.:

Cov.:

AF XY:

0.00000286

AC XY:

AN XY:

698492

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31684

American (AMR)

AF:

0.00

AC:

AN:

40570

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25080

East Asian (EAS)

AF:

0.00

AC:

AN:

37140

South Asian (SAS)

AF:

0.00

AC:

AN:

82600

European-Finnish (FIN)

AF:

0.00

AC:

AN:

41232

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5320

European-Non Finnish (NFE)

AF:

0.00000184

AC:

AN:

1088134

Other (OTH)

AF:

0.00

AC:

AN:

58272

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

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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.36

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.52

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.21

Eigen

Benign

-0.15

Eigen_PC

Benign

-0.17

FATHMM_MKL

Benign

0.28

LIST_S2

Benign

0.84

M_CAP

Uncertain

0.18

MetaRNN

Benign

0.20

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.1

PhyloP100

5.4

PrimateAI

Pathogenic

0.97

PROVEAN

Benign

-0.94

REVEL

Benign

0.15

Sift

Benign

0.25

Sift4G

Benign

0.11

Polyphen

0.45

Vest4

0.29

MutPred

0.41

Loss of sheet (P = 0.0037);

MVP

0.46

MPC

1.4

ClinPred

0.47

GERP RS

-1.7

PromoterAI

0.011

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.26

gMVP

0.38

Mutation Taster

=92/8

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over