NM_001130145.3:c.20C>T

Variant names:

• chr11-102110868-C-T
• rs1025759993
• NM_001130145.3:c.20C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001130145.3(YAP1):​c.20C>T​(p.Pro7Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000282 in 1,416,224 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. P7P) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000024 (0 hom.)
• Consequence: YAP1 NM_001130145.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.159
• 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: Orphanet, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.064727485).

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.20C>T	p.Pro7Leu	missense	Exon 1 of 9	NP_001123617.1	P46937-1
	YAP1	NM_001282101.2		c.20C>T	p.Pro7Leu	missense	Exon 1 of 9	NP_001269030.1	P46937-9
	YAP1	NM_001282100.2		c.20C>T	p.Pro7Leu	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.20C>T	p.Pro7Leu	missense	Exon 1 of 9	ENSP00000282441.5	P46937-1
	YAP1	ENST00000531439.5	TSL:1	c.20C>T	p.Pro7Leu	missense	Exon 1 of 8	ENSP00000431574.1	P46937-2
	YAP1	ENST00000951261.1		c.20C>T	p.Pro7Leu	missense	Exon 1 of 10	ENSP00000621320.1

Frequencies

GnomAD3 genomes AF: 0.00000660 AC: 1 AN: 151620 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000237 AC: 3 AN: 1264604 Hom.: 0 Cov.: 31 AF XY: 0.00000321 AC XY: 2 AN XY: 622796

African (AFR) AF: 0.0000393 AC: 1 AN: 25466

American (AMR) AF: 0.00 AC: 0 AN: 22354

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20970

East Asian (EAS) AF: 0.00 AC: 0 AN: 25900

South Asian (SAS) AF: 0.00 AC: 0 AN: 64664

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34918

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3598

European-Non Finnish (NFE) AF: 0.00000197 AC: 2 AN: 1015606

Other (OTH) AF: 0.00 AC: 0 AN: 51128

GnomAD4 genome AF: 0.00000660 AC: 1 AN: 151620 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74038

African (AFR) AF: 0.0000242 AC: 1 AN: 41388

American (AMR) AF: 0.00 AC: 0 AN: 15216

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5150

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67848

Other (OTH) AF: 0.00 AC: 0 AN: 2082

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.61	T
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.065	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L
PhyloP100		0.16
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.46	N
REVEL	Benign	0.031
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.21	T
Polyphen		0.0090	B
Vest4		0.20
MutPred		0.28		Gain of stability (P = 0.0182)
MVP		0.043
MPC		1.2
ClinPred		0.41	T
GERP RS		1.4
PromoterAI		-0.019	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.3
Varity_R		0.035
gMVP		0.16
Mutation Taster		=91/9	polymorphism

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: rs1025759993; hg19: chr11-101981599;