rs1131692044

Positions:

• chr14-100277451-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PM5 PP2 PP5

The NM_003403.5(YY1):​c.1096C>G​(p.Leu366Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L366P) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: YY1 NM_003403.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 4.12

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]

MIR6764 (HGNC:49994): (microRNA 6764) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr14-100277452-T-C is described in Lovd as [Pathogenic].
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), YY1. . Gene score misZ 3.3086 (greater than the threshold 3.09). Trascript score misZ 3.5888 (greater than threshold 3.09). GenCC has associacion of gene with Gabriele de Vries syndrome, intellectual disability, autosomal dominant 40.
• PP5: Variant 14-100277451-C-G is Pathogenic according to our data. Variant chr14-100277451-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 430619.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
YY1	NM_003403.5	c.1096C>G	p.Leu366Val	missense_variant	5/5	ENST00000262238.10	NP_003394.1
MIR6764	NR_106822.1			downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
YY1	ENST00000262238.10	c.1096C>G	p.Leu366Val	missense_variant	5/5	1	NM_003403.5	ENSP00000262238	P1
MIR6764	ENST00000636393.1			downstream_gene_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Gabriele de Vries syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 17, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Benign	-0.016	T
BayesDel_noAF	Benign	-0.26
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.67	D
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.018	T
MetaRNN	Uncertain	0.56	D
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.030	N
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.93	D
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.24
Sift	Uncertain	0.017	D
Sift4G	Uncertain	0.031	D
Polyphen		1.0	D
Vest4		0.62
MutPred		0.41		Gain of catalytic residue at R363 (P = 0);
MVP		0.59
MPC		3.4
ClinPred		0.95	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.66
gMVP		0.92

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

LitVar

Other links and lift over

dbSNP: rs1131692044; hg19: chr14-100743788;