11-102111153-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001130145.3(YAP1):c.305A>T(p.Lys102Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,744 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: 0.0000014 (0 hom.)
• Consequence: YAP1 NM_001130145.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.590

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15557271).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
YAP1	NM_001130145.3	c.305A>T	p.Lys102Ile	missense_variant	1/9	ENST00000282441.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
YAP1	ENST00000282441.10	c.305A>T	p.Lys102Ile	missense_variant	1/9	1	NM_001130145.3	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460744 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726714

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 17, 2022

The c.305A>T (p.K102I) alteration is located in exon 1 (coding exon 1) of the YAP1 gene. This alteration results from a A to T substitution at nucleotide position 305, causing the lysine (K) at amino acid position 102 to be replaced by an isoleucine (I). 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	Pathogenic	0.95
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
Cadd	Benign	23
Dann	Benign	0.94
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.69	D
LIST_S2	Uncertain	0.90	D;D;D;D;D;D;D
M_CAP	Pathogenic	0.66	D
MetaRNN	Benign	0.16	T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L;L;L;L;L;L;L
MutationTaster	Benign	0.99	D;D;D;D;D
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-1.6	N;N;N;N;.;.;N
REVEL	Benign	0.063
Sift	Benign	0.25	T;T;T;T;.;.;T
Sift4G	Benign	0.11	T;T;T;T;T;T;T
Polyphen		0.58, 0.053, 0.025	.;P;.;.;.;B;B
Vest4		0.28
MutPred		0.35		Loss of ubiquitination at K102 (P = 0.0019);Loss of ubiquitination at K102 (P = 0.0019);Loss of ubiquitination at K102 (P = 0.0019);Loss of ubiquitination at K102 (P = 0.0019);Loss of ubiquitination at K102 (P = 0.0019);Loss of ubiquitination at K102 (P = 0.0019);Loss of ubiquitination at K102 (P = 0.0019);
MVP		0.068
MPC		0.71
ClinPred		0.63	D
GERP RS		2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.27
gMVP		0.47

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-101981884;