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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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