chr11-102111105-T-C

Variant names:

• chr11-102111105-T-C
• rs2135086778
• NM_001130145.3:c.257T>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM2 PP5_Moderate BP4

The NM_001130145.3(YAP1):​c.257T>C​(p.Met86Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: YAP1 NM_001130145.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.12
• Publications: 0 publications found

Genes affected

YAP1 (HGNC:16262): (Yes1 associated transcriptional regulator) This gene encodes a downstream nuclear effector of the Hippo signaling pathway which is involved in development, growth, repair, and homeostasis. This gene is known to play a role in the development and progression of multiple cancers as a transcriptional regulator of this signaling pathway and may function as a potential target for cancer treatment. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Aug 2013]

YAP1 Gene-Disease associations (from GenCC):

• uveal coloboma-cleft lip and palate-intellectual disability

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Orphanet, G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-102111105-T-C is Pathogenic according to our data. Variant chr11-102111105-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 1686307.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.2562431). . Strength limited to SUPPORTING due to the PP5.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001130145.3. 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
	YAP1	NM_001130145.3	MANE Select	c.257T>C	p.Met86Thr	missense	Exon 1 of 9	NP_001123617.1	P46937-1
	YAP1	NM_001282101.2		c.257T>C	p.Met86Thr	missense	Exon 1 of 9	NP_001269030.1	P46937-9
	YAP1	NM_001282100.2		c.257T>C	p.Met86Thr	missense	Exon 1 of 8	NP_001269029.1	P46937-8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	YAP1	ENST00000282441.10	TSL:1 MANE Select	c.257T>C	p.Met86Thr	missense	Exon 1 of 9	ENSP00000282441.5	P46937-1
	YAP1	ENST00000531439.5	TSL:1	c.257T>C	p.Met86Thr	missense	Exon 1 of 8	ENSP00000431574.1	P46937-2
	YAP1	ENST00000951261.1		c.257T>C	p.Met86Thr	missense	Exon 1 of 10	ENSP00000621320.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Uveal coloboma-cleft lip and palate-intellectual disability (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Benign	-0.059	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	22
DANN	Benign	0.95
DEOGEN2	Uncertain	0.65	D
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.54	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.70	D
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		2.1
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.14
Sift	Benign	0.036	D
Sift4G	Benign	0.36	T
Polyphen		0.097	B
Vest4		0.36
MutPred		0.35		Gain of glycosylation at M86 (P = 0.0155)
MVP		0.18
MPC		1.5
ClinPred		0.56	D
GERP RS		2.7
PromoterAI		-0.081	Neutral
Varity_R		0.76
gMVP		0.62
Mutation Taster		=15/85	disease causing

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: rs2135086778; hg19: chr11-101981836;