NM_198173.3:c.738C>T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong

The NM_198173.3(GRHL3):c.738C>T(p.Gly246Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

GRHL3
NM_198173.3 synonymous

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3U:1

Conservation

PhyloP100: -2.70

Publications

4 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):

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

GRHL3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 1-24337687-C-T is Pathogenic according to our data. Variant chr1-24337687-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 219243.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-24337687-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 219243.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-24337687-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 219243.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-24337687-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 219243.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-24337687-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 219243.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-24337687-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 219243.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-24337687-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 219243.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-24337687-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 219243.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-24337687-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 219243.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-24337687-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 219243.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-24337687-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 219243.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-24337687-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 219243.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-24337687-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 219243.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-24337687-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 219243.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRHL3	NM_198173.3 link	c.738C>T	p.Gly246Gly	synonymous_variant	Exon 6 of 16	ENST00000361548.9	NP_937816.1	Q8TE85-5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRHL3	ENST00000361548.9 link	c.738C>T	p.Gly246Gly	synonymous_variant	Exon 6 of 16	1	NM_198173.3	ENSP00000354943.5		Q8TE85-5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251338

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461890

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727246

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1112010

Other (OTH)

AF:

0.00

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:1

Feb 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 06, 2024

GeneDx

Significance:Uncertain significance

Review Status:flagged submission

Collection Method:clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 31785789, 28714951, 35982159, 35982160, 27018475) -

Isolated cleft palate

Pathogenic:1

Dec 01, 2015

Ludwig Lab, Institute of Human Genetics, University Hospital Bonn

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Van der Woude syndrome 2

Pathogenic:1

Feb 20, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change affects codon 246 of the GRHL3 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the GRHL3 protein. This variant is present in population databases (no rsID available, gnomAD 0.004%). This variant has been observed in individual(s) with GRHL3-related conditions (PMID: 27018475). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 219243). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.52

CADD

Benign

(source)

DANN

Benign

0.51

PhyloP100

-2.7

Mutation Taster

=98/2

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.69

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.69

Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over