1-24347482-CGGAG-C

Variant names:

• chr1-24347482-CGGAG-C
• rs879255243
• NM_198173.3:c.1563_1566delGGAG

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_198173.3(GRHL3):​c.1563_1566delGGAG​(p.Glu522LeufsTer10) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GRHL3 NM_198173.3 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.60
• Publications: 0 publications found

Genes affected

GRHL3 (HGNC:25839): (grainyhead like transcription factor 3) This gene encodes a member of the grainyhead family of transcription factors. The encoded protein may function as a transcription factor during development, and has been shown to stimulate migration of endothelial cells. Multiple transcript variants encoding distinct isoforms have been identified for this gene.[provided by RefSeq, Aug 2010]

GRHL3 Gene-Disease associations (from GenCC):

• van der Woude syndrome 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• van der Woude syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-24347482-CGGAG-C is Pathogenic according to our data. Variant chr1-24347482-CGGAG-C is described in ClinVar as Pathogenic. ClinVar VariationId is 101517.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198173.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRHL3	NM_198173.3	MANE Select	c.1563_1566delGGAG	p.Glu522LeufsTer10	frameshift	Exon 14 of 16	NP_937816.1
	GRHL3	NM_198174.3		c.1563_1566delGGAG	p.Glu522LeufsTer10	frameshift	Exon 14 of 16	NP_937817.3
	GRHL3	NM_021180.4		c.1578_1581delGGAG	p.Glu527LeufsTer10	frameshift	Exon 14 of 16	NP_067003.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRHL3	ENST00000361548.9	TSL:1 MANE Select	c.1563_1566delGGAG	p.Glu522LeufsTer10	frameshift	Exon 14 of 16	ENSP00000354943.5
	GRHL3	ENST00000236255.4	TSL:1	c.1578_1581delGGAG	p.Glu527LeufsTer10	frameshift	Exon 14 of 16	ENSP00000236255.4
	GRHL3	ENST00000356046.6	TSL:1	c.1425_1428delGGAG	p.Glu476LeufsTer10	frameshift	Exon 14 of 16	ENSP00000348333.2

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Van der Woude syndrome 2 Pathogenic:1

Jan 02, 2014

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.6
Mutation Taster		=1/199	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs879255243; hg19: chr1-24673972;