rs1942859608

Variant names:

• chr11-102110971-CCAGGCGGCGCCG-C
• rs1942859608
• NM_001130145.3:c.129_140delGGCGCCGCAGGC

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM4

The NM_001130145.3(YAP1):​c.129_140delGGCGCCGCAGGC​(p.Ala44_Ala47del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000985 in 1,522,228 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: YAP1 NM_001130145.3 disruptive_inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 3.50
• 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: Labcorp Genetics (formerly Invitae), PanelApp Australia, Orphanet, G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_001130145.3.

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.129_140delGGCGCCGCAGGC	p.Ala44_Ala47del	disruptive_inframe_deletion	Exon 1 of 9	NP_001123617.1	P46937-1
	YAP1	NM_001282101.2		c.129_140delGGCGCCGCAGGC	p.Ala44_Ala47del	disruptive_inframe_deletion	Exon 1 of 9	NP_001269030.1	P46937-9
	YAP1	NM_001282100.2		c.129_140delGGCGCCGCAGGC	p.Ala44_Ala47del	disruptive_inframe_deletion	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.129_140delGGCGCCGCAGGC	p.Ala44_Ala47del	disruptive_inframe_deletion	Exon 1 of 9	ENSP00000282441.5	P46937-1
	YAP1	ENST00000531439.5	TSL:1	c.129_140delGGCGCCGCAGGC	p.Ala44_Ala47del	disruptive_inframe_deletion	Exon 1 of 8	ENSP00000431574.1	P46937-2
	YAP1	ENST00000951261.1		c.129_140delGGCGCCGCAGGC	p.Ala44_Ala47del	disruptive_inframe_deletion	Exon 1 of 10	ENSP00000621320.1

Frequencies

GnomAD3 genomes AF: 0.00000660 AC: 1 AN: 151422 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000148

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000102 AC: 14 AN: 1370806 Hom.: 0 AF XY: 0.0000118 AC XY: 8 AN XY: 676584

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000360 AC: 1 AN: 27750

American (AMR) AF: 0.00 AC: 0 AN: 32686

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23990

East Asian (EAS) AF: 0.00 AC: 0 AN: 31072

South Asian (SAS) AF: 0.00 AC: 0 AN: 77804

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47630

Middle Eastern (MID) AF: 0.000707 AC: 3 AN: 4244

European-Non Finnish (NFE) AF: 0.00000935 AC: 10 AN: 1069078

Other (OTH) AF: 0.00 AC: 0 AN: 56552

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000443809), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000660 AC: 1 AN: 151422 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 73958

African (AFR) AF: 0.00 AC: 0 AN: 41248

American (AMR) AF: 0.00 AC: 0 AN: 15214

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5076

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10532

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 304

European-Non Finnish (NFE) AF: 0.0000148 AC: 1 AN: 67776

Other (OTH) AF: 0.00 AC: 0 AN: 2080

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)
-	1	-	YAP1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.5
Mutation Taster		=158/42	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1942859608; hg19: chr11-101981702;