11-102110903-C-T

Variant names:

• chr11-102110903-C-T
• rs1402910700
• NM_001130145.3:c.55C>T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001130145.3(YAP1):​c.55C>T​(p.Pro19Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000467 in 1,283,476 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000047 (0 hom.)
• Consequence: YAP1 NM_001130145.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.240

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]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.11285931).
• BS2: High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
YAP1	NM_001130145.3	c.55C>T	p.Pro19Ser	missense_variant	Exon 1 of 9	ENST00000282441.10	NP_001123617.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
YAP1	ENST00000282441.10	c.55C>T	p.Pro19Ser	missense_variant	Exon 1 of 9	1	NM_001130145.3	ENSP00000282441.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000467 AC: 6 AN: 1283476 Hom.: 0 Cov.: 31 AF XY: 0.00000633 AC XY: 4 AN XY: 632362

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000151

Gnomad4 FIN exome AF: 0.0000241

Gnomad4 NFE exome AF: 0.00000292

Gnomad4 OTH exome AF: 0.0000192

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 27, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.55C>T (p.P19S) alteration is located in exon 1 (coding exon 1) of the YAP1 gene. This alteration results from a C to T substitution at nucleotide position 55, causing the proline (P) at amino acid position 19 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.14	.;T;.;.;.;.;.
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.80	T;T;T;T;T;T;T
M_CAP	Pathogenic	0.39	D
MetaRNN	Benign	0.11	T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L;L;L;L;L;L;L
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.62	N;N;N;N;.;.;N
REVEL	Benign	0.056
Sift	Pathogenic	0.0	D;D;D;D;.;.;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D
Polyphen		0.0, 0.0010	.;B;.;.;.;B;B
Vest4		0.14
MutPred		0.30		Loss of catalytic residue at P19 (P = 0.0045);Loss of catalytic residue at P19 (P = 0.0045);Loss of catalytic residue at P19 (P = 0.0045);Loss of catalytic residue at P19 (P = 0.0045);Loss of catalytic residue at P19 (P = 0.0045);Loss of catalytic residue at P19 (P = 0.0045);Loss of catalytic residue at P19 (P = 0.0045);
MVP		0.043
MPC		1.2
ClinPred		0.67	D
GERP RS		1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.0
Varity_R		0.099
gMVP		0.37

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: rs1402910700; hg19: chr11-101981634;