11-102111161-T-C

Position:

chr11-102111161-T-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM1BP4BS2

The NM_001130145.3(YAP1):c.313T>C(p.Ser105Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000161 in 1,612,178 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

YAP1
NM_001130145.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 3.18

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM1

In a modified_residue Phosphoserine (size 0) in uniprot entity YAP1_HUMAN

BP4

Computational evidence support a benign effect (MetaRNN=0.29828903).

BS2

High AC in GnomAdExome4 at 23 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
YAP1	NM_001130145.3 linkuse as main transcript	c.313T>C	p.Ser105Pro	missense_variant	1/9	ENST00000282441.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
YAP1	ENST00000282441.10 linkuse as main transcript	c.313T>C	p.Ser105Pro	missense_variant	1/9	1	NM_001130145.3	P2	P46937-1

Frequencies

GnomAD3 genomes

AF:

0.0000198

AC:

AN:

151860

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000123

AC:

AN:

244788

Hom.:

AF XY:

0.0000149

AC XY:

AN XY:

133958

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000914

Gnomad OTH exome

AF:

0.000167

GnomAD4 exome

AF:

0.0000157

AC:

AN:

1460318

Hom.:

Cov.:

AF XY:

0.0000206

AC XY:

AN XY:

726546

show subpopulations

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:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000144

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000198

AC:

AN:

151860

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74154

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 22, 2023

The c.313T>C (p.S105P) alteration is located in exon 1 (coding exon 1) of the YAP1 gene. This alteration results from a T to C substitution at nucleotide position 313, causing the serine (S) at amino acid position 105 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

YAP1-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 26, 2023

The YAP1 c.313T>C variant is predicted to result in the amino acid substitution p.Ser105Pro. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0033% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-101981892-T-C). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 08, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt YAP1 protein function. This variant has not been reported in the literature in individuals affected with YAP1-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 105 of the YAP1 protein (p.Ser105Pro). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.34

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.79

.;D;.;.;.;.;.

Eigen

Benign

0.077

Eigen_PC

Benign

-0.050

FATHMM_MKL

Uncertain

0.79

LIST_S2

Uncertain

0.94

D;D;D;D;D;D;D

M_CAP

Pathogenic

0.78

MetaRNN

Benign

0.30

T;T;T;T;T;T;T

MetaSVM

Benign

-0.74

MutationAssessor

Uncertain

2.4

M;M;M;M;M;M;M

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Pathogenic

0.84

PROVEAN

Uncertain

-3.8

D;D;D;D;.;.;D

REVEL

Benign

0.12

Sift

Uncertain

0.0020

D;D;D;D;.;.;D

Sift4G

Uncertain

0.0060

D;D;D;D;D;D;D

Polyphen

0.96, 0.99, 0.99

.;P;.;.;.;D;D

Vest4

0.13

MutPred

0.20

Loss of phosphorylation at S105 (P = 0.0187);Loss of phosphorylation at S105 (P = 0.0187);Loss of phosphorylation at S105 (P = 0.0187);Loss of phosphorylation at S105 (P = 0.0187);Loss of phosphorylation at S105 (P = 0.0187);Loss of phosphorylation at S105 (P = 0.0187);Loss of phosphorylation at S105 (P = 0.0187);

MVP

0.23

MPC

0.65

ClinPred

0.66

GERP RS

1.3

Varity_R

0.70

gMVP

0.60

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over