1-24354474-C-G

Variant names:

• chr1-24354474-C-G
• rs797044857
• NM_198173.3:c.1795C>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP5_Moderate

The NM_198173.3(GRHL3):​c.1795C>G​(p.Leu599Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GRHL3 NM_198173.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.61
• Publications: 1 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: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• van der Woude syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-24354474-C-G is Pathogenic according to our data. Variant chr1-24354474-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 208652.Status of the report is criteria_provided_single_submitter, 1 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRHL3	NM_198173.3	MANE Select	c.1795C>G	p.Leu599Val	missense	Exon 16 of 16	NP_937816.1	Q8TE85-5
	GRHL3	NM_021180.4		c.1810C>G	p.Leu604Val	missense	Exon 16 of 16	NP_067003.2
	GRHL3	NM_001195010.2		c.1657C>G	p.Leu553Val	missense	Exon 16 of 16	NP_001181939.1	Q8TE85-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRHL3	ENST00000361548.9	TSL:1 MANE Select	c.1795C>G	p.Leu599Val	missense	Exon 16 of 16	ENSP00000354943.5	Q8TE85-5
	GRHL3	ENST00000236255.4	TSL:1	c.1810C>G	p.Leu604Val	missense	Exon 16 of 16	ENSP00000236255.4	Q8TE85-2
	GRHL3	ENST00000356046.6	TSL:1	c.1657C>G	p.Leu553Val	missense	Exon 16 of 16	ENSP00000348333.2	Q8TE85-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Benign	-0.051	T
BayesDel_noAF	Benign	-0.31
CADD	Uncertain	26
DANN	Uncertain	1.0
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.036	D
MetaRNN	Uncertain	0.64	D
MetaSVM	Benign	-0.80	T
PhyloP100		6.6
PROVEAN	Uncertain	-2.5	N
REVEL	Uncertain	0.30
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.71
MutPred		0.53		Gain of methylation at K605 (P = 0.0315)
MVP		0.24
ClinPred		0.93	D
GERP RS		4.8
Mutation Taster		=6/94	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: rs797044857; hg19: chr1-24680964;