Genetic Variant GRHL3:p.Leu599Val (chr1-24354474-C-G) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is . The variant received 4 ACMG points: 4P and 0B. PM2PP5_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

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 6.61

Publications

1 publications found

Variant links:

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):

GRHL3-related orofacial clefting
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
van der Woude syndrome 2
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia
van der Woude syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

GRHL3 links:

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new If you want to explore the variant's impact on the transcript NM_198173.3, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

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

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

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.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Likely pathogenic

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.82

BayesDel_addAF

Benign

-0.051

BayesDel_noAF

Benign

-0.31

CADD

Uncertain

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

0.69

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.91

M_CAP

Benign

0.036

MetaRNN

Uncertain

0.64

MetaSVM

Benign

-0.80

PhyloP100

6.6

PROVEAN

Uncertain

-2.5

REVEL

Uncertain

0.30

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Mutation Taster

=6/94

disease causing (ClinVar)

(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

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

Publications

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GRHL3 p.Leu599Val

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over