rs1131692044

Variant names:

• chr14-100277451-C-G
• rs1131692044
• NM_003403.5:c.1096C>G

Your query was ambiguous. Multiple possible variants found:

• chr14-100277451-C-G
• chr14-100277451-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 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
• Publications: 3 publications found

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

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_003403.5
• 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 ClinVar as Pathogenic. ClinVar VariationId is 430618.Status of the report is no_assertion_criteria_provided, 0 stars.
• 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.
• PP5: Variant 14-100277451-C-G is Pathogenic according to our data. Variant chr14-100277451-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 430619.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003403.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	YY1	NM_003403.5	MANE Select	c.1096C>G	p.Leu366Val	missense	Exon 5 of 5	NP_003394.1
	MIR6764	NR_106822.1		n.*34C>G		downstream_gene	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	YY1	ENST00000262238.10	TSL:1 MANE Select	c.1096C>G	p.Leu366Val	missense	Exon 5 of 5	ENSP00000262238.4
	YY1	ENST00000554804.1	TSL:3	c.421C>G	p.Leu141Val	missense	Exon 4 of 4	ENSP00000452225.1
	YY1	ENST00000704485.1		c.334C>G	p.Leu112Val	missense	Exon 5 of 5	ENSP00000515913.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Gabriele de Vries syndrome (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		4.1
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
Mutation Taster		=33/67	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1131692044; hg19: chr14-100743788;