1-24337687-C-G

Variant names:

• chr1-24337687-C-G
• NM_198173.3:c.738C>G
• GRHL3 p.Gly246Gly

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_198173.3(GRHL3):​c.738C>G​(p.Gly246Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. G246G) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GRHL3 NM_198173.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.70
• 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• van der Woude syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP7: Synonymous conserved (PhyloP=-2.7 with no splicing effect.

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.738C>G	p.Gly246Gly	synonymous	Exon 6 of 16	NP_937816.1	Q8TE85-5
	GRHL3	NM_198174.3		c.738C>G	p.Gly246Gly	synonymous	Exon 6 of 16	NP_937817.3
	GRHL3	NM_021180.4		c.753C>G	p.Gly251Gly	synonymous	Exon 6 of 16	NP_067003.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRHL3	ENST00000361548.9	TSL:1 MANE Select	c.738C>G	p.Gly246Gly	synonymous	Exon 6 of 16	ENSP00000354943.5	Q8TE85-5
	GRHL3	ENST00000236255.4	TSL:1	c.753C>G	p.Gly251Gly	synonymous	Exon 6 of 16	ENSP00000236255.4	Q8TE85-2
	GRHL3	ENST00000356046.6	TSL:1	c.600C>G	p.Gly200Gly	synonymous	Exon 6 of 16	ENSP00000348333.2	Q8TE85-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	3.2
DANN	Benign	0.54
PhyloP100		-2.7
Mutation Taster		=98/2	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr1-24664177;