NM_198173.3:c.1361C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_198173.3(GRHL3):c.1361C>T(p.Thr454Met) variant causes a missense change. The variant allele was found at a frequency of 0.0304 in 1,614,014 control chromosomes in the GnomAD database, including 967 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.022 ( 55 hom., cov: 32)

Exomes 𝑓: 0.031 ( 912 hom. )

Consequence

GRHL3
NM_198173.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 6.00

Publications

45 publications found

Variant links:

COSMIC-nc: COSV107246498

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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0035236776).

BP6

Variant 1-24342967-C-T is Benign according to our data. Variant chr1-24342967-C-T is described in ClinVar as Benign. ClinVar VariationId is 465245.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0224 (3402/152148) while in subpopulation NFE AF = 0.0337 (2290/67998). AF 95% confidence interval is 0.0325. There are 55 homozygotes in GnomAd4. There are 1686 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 3402 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRHL3	NM_198173.3 link	c.1361C>T	p.Thr454Met	missense_variant	Exon 11 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.1361C>T	p.Thr454Met	missense_variant	Exon 11 of 16	1	NM_198173.3	ENSP00000354943.5		Q8TE85-5

Frequencies

GnomAD3 genomes

AF:

0.0224

AC:

3403

AN:

152030

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00590

Gnomad AMI

AF:

0.0209

Gnomad AMR

AF:

0.0130

Gnomad ASJ

AF:

0.00374

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00957

Gnomad FIN

AF:

0.0513

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0337

Gnomad OTH

AF:

0.0211

GnomAD2 exomes

AF:

0.0228

AC:

5744

AN:

251466

AF XY:

0.0231

show subpopulations

Gnomad AFR exome

AF:

0.00597

Gnomad AMR exome

AF:

0.0107

Gnomad ASJ exome

AF:

0.00615

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.0540

Gnomad NFE exome

AF:

0.0321

Gnomad OTH exome

AF:

0.0236

GnomAD4 exome

AF:

0.0313

AC:

45693

AN:

1461866

Hom.:

912

Cov.:

AF XY:

0.0309

AC XY:

22497

AN XY:

727238

show subpopulations

African (AFR)

AF:

0.00517

AC:

173

AN:

33480

American (AMR)

AF:

0.0113

AC:

505

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00547

AC:

143

AN:

26136

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39700

South Asian (SAS)

AF:

0.00845

AC:

729

AN:

86256

European-Finnish (FIN)

AF:

0.0525

AC:

2805

AN:

53416

Middle Eastern (MID)

AF:

0.0179

AC:

103

AN:

5768

European-Non Finnish (NFE)

AF:

0.0356

AC:

39603

AN:

1111990

Other (OTH)

AF:

0.0270

AC:

1629

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

2506

5013

7519

10026

12532

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1488

2976

4464

5952

7440

<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

AF:

0.0224

AC:

3402

AN:

152148

Hom.:

Cov.:

AF XY:

0.0227

AC XY:

1686

AN XY:

74374

show subpopulations

African (AFR)

AF:

0.00590

AC:

245

AN:

41506

American (AMR)

AF:

0.0129

AC:

198

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00374

AC:

AN:

3472

East Asian (EAS)

AF:

0.000194

AC:

AN:

5158

South Asian (SAS)

AF:

0.00916

AC:

AN:

4804

European-Finnish (FIN)

AF:

0.0513

AC:

544

AN:

10602

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0337

AC:

2290

AN:

67998

Other (OTH)

AF:

0.0209

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

167

334

501

668

835

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

126

168

210

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0285

Hom.:

264

Bravo

AF:

0.0194

TwinsUK

AF:

0.0343

AC:

127

ALSPAC

AF:

0.0394

AC:

152

ESP6500AA

AF:

0.00613

AC:

ESP6500EA

AF:

0.0317

AC:

273

ExAC

AF:

0.0228

AC:

2765

Asia WGS

AF:

0.00260

AC:

AN:

3476

EpiCase

AF:

0.0293

EpiControl

AF:

0.0292

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

May 04, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 27018475, 27018472, 28886269) -

Van der Woude syndrome 2

Benign:1

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.43

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.70

.;D;.;.

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Uncertain

0.95

LIST_S2

Pathogenic

0.98

D;D;D;D

MetaRNN

Benign

0.0035

T;T;T;T

MetaSVM

Benign

-1.2

MutationAssessor

Uncertain

2.6

M;M;.;.

PhyloP100

6.0

PrimateAI

Benign

0.48

PROVEAN

Uncertain

-3.1

D;D;D;D

REVEL

Benign

0.18

Sift

Uncertain

0.0040

D;D;D;D

Sift4G

Uncertain

0.017

D;D;D;D

Polyphen

1.0

.;.;.;D

Vest4

0.34

MPC

1.1

ClinPred

0.0095

GERP RS

4.3

Varity_R

0.28

gMVP

0.36

Mutation Taster

=96/4

polymorphism (auto)

(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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over