Genetic Variant NM_001130145.3:c.11G>C (chr11-102110859-G-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001130145.3(YAP1):c.11G>C(p.Gly4Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000793 in 1,261,776 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G4E) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.9e-7 ( 0 hom. )

Consequence

YAP1
NM_001130145.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.249

Publications

1 publications found

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 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

YAP1 links:

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ACMG classification

Classification was made for transcript

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=0.043026358).

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
YAP1	NM_001130145.3	MANE Select	c.11G>C	p.Gly4Ala	missense	Exon 1 of 9	NP_001123617.1	P46937-1
YAP1	NM_001282101.2		c.11G>C	p.Gly4Ala	missense	Exon 1 of 9	NP_001269030.1	P46937-9
YAP1	NM_001282100.2		c.11G>C	p.Gly4Ala	missense	Exon 1 of 8	NP_001269029.1	P46937-8

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
YAP1	ENST00000282441.10	TSL:1 MANE Select	c.11G>C	p.Gly4Ala	missense	Exon 1 of 9	ENSP00000282441.5	P46937-1
YAP1	ENST00000531439.5	TSL:1	c.11G>C	p.Gly4Ala	missense	Exon 1 of 8	ENSP00000431574.1	P46937-2
YAP1	ENST00000951261.1		c.11G>C	p.Gly4Ala	missense	Exon 1 of 10	ENSP00000621320.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.93e-7

AC:

AN:

1261776

Hom.:

Cov.:

AF XY:

0.00000161

AC XY:

AN XY:

621494

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25400

American (AMR)

AF:

0.00

AC:

AN:

22240

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20888

East Asian (EAS)

AF:

0.00

AC:

AN:

25782

South Asian (SAS)

AF:

0.00

AC:

AN:

64680

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33426

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3594

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1014740

Other (OTH)

AF:

0.0000196

AC:

AN:

51026

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.57

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.14

Eigen

Benign

-0.88

Eigen_PC

Benign

-0.78

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.82

M_CAP

Uncertain

0.17

MetaRNN

Benign

0.043

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.0

PhyloP100

-0.25

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

-0.66

REVEL

Benign

0.076

Sift

Pathogenic

0.0

Sift4G

Benign

0.58

Polyphen

0.0

Vest4

0.055

MutPred

0.17

Gain of glycosylation at P7 (P = 0.1525)

MVP

0.068

MPC

1.3

ClinPred

0.15

GERP RS

-0.10

PromoterAI

-0.038

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.3

Varity_R

0.16

gMVP

0.15

Mutation Taster

=85/15

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over