NM_198173.3:c.165C>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_198173.3(GRHL3):c.165C>G(p.Asp55Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.167 in 1,613,514 control chromosomes in the GnomAD database, including 23,185 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.17 ( 2319 hom., cov: 32)

Exomes 𝑓: 0.17 ( 20866 hom. )

Consequence

GRHL3
NM_198173.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.461

Publications

21 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0013997555).

BP6

Variant 1-24331573-C-G is Benign according to our data. Variant chr1-24331573-C-G is described in ClinVar as Benign. ClinVar VariationId is 1120074.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.202 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRHL3	NM_198173.3 link	c.165C>G	p.Asp55Glu	missense_variant	Exon 2 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.165C>G	p.Asp55Glu	missense_variant	Exon 2 of 16	1	NM_198173.3	ENSP00000354943.5		Q8TE85-5

Frequencies

GnomAD3 genomes

AF:

0.170

AC:

25869

AN:

152002

Hom.:

2314

Cov.:

show subpopulations

Gnomad AFR

AF:

0.206

Gnomad AMI

AF:

0.154

Gnomad AMR

AF:

0.126

Gnomad ASJ

AF:

0.107

Gnomad EAS

AF:

0.193

Gnomad SAS

AF:

0.148

Gnomad FIN

AF:

0.156

Gnomad MID

AF:

0.0443

Gnomad NFE

AF:

0.165

Gnomad OTH

AF:

0.155

GnomAD2 exomes

AF:

0.158

AC:

39675

AN:

251202

AF XY:

0.155

show subpopulations

Gnomad AFR exome

AF:

0.206

Gnomad AMR exome

AF:

0.139

Gnomad ASJ exome

AF:

0.109

Gnomad EAS exome

AF:

0.191

Gnomad FIN exome

AF:

0.155

Gnomad NFE exome

AF:

0.161

Gnomad OTH exome

AF:

0.147

GnomAD4 exome

AF:

0.167

AC:

243937

AN:

1461394

Hom.:

20866

Cov.:

AF XY:

0.165

AC XY:

120267

AN XY:

727028

show subpopulations

African (AFR)

AF:

0.197

AC:

6595

AN:

33472

American (AMR)

AF:

0.137

AC:

6115

AN:

44702

Ashkenazi Jewish (ASJ)

AF:

0.111

AC:

2899

AN:

26126

East Asian (EAS)

AF:

0.164

AC:

6506

AN:

39696

South Asian (SAS)

AF:

0.143

AC:

12332

AN:

86204

European-Finnish (FIN)

AF:

0.154

AC:

8236

AN:

53418

Middle Eastern (MID)

AF:

0.0624

AC:

360

AN:

5766

European-Non Finnish (NFE)

AF:

0.172

AC:

190809

AN:

1111628

Other (OTH)

AF:

0.167

AC:

10085

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

9561

19122

28682

38243

47804

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6908

13816

20724

27632

34540

<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:

0.170

AC:

25883

AN:

152120

Hom.:

2319

Cov.:

AF XY:

0.166

AC XY:

12371

AN XY:

74370

show subpopulations

African (AFR)

AF:

0.206

AC:

8534

AN:

41478

American (AMR)

AF:

0.126

AC:

1931

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.107

AC:

370

AN:

3468

East Asian (EAS)

AF:

0.193

AC:

997

AN:

5162

South Asian (SAS)

AF:

0.148

AC:

714

AN:

4822

European-Finnish (FIN)

AF:

0.156

AC:

1654

AN:

10594

Middle Eastern (MID)

AF:

0.0408

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.165

AC:

11208

AN:

67990

Other (OTH)

AF:

0.153

AC:

323

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1077

2153

3230

4306

5383

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

288

576

864

1152

1440

<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:

0.160

Hom.:

1512

Bravo

AF:

0.171

TwinsUK

AF:

0.173

AC:

640

ALSPAC

AF:

0.170

AC:

656

ESP6500AA

AF:

0.207

AC:

911

ESP6500EA

AF:

0.164

AC:

1414

ExAC

AF:

0.159

AC:

19347

Asia WGS

AF:

0.169

AC:

588

AN:

3478

EpiCase

AF:

0.148

EpiControl

AF:

0.148

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Feb 18, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 31332962) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

Feb 08, 2021

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Asp55Glu variant in GRHL3 is classified as benign because it has been identified in 15.97% (4526/282536) of total chromosomes in gnomAD, including 3777 homozygous individuals (http://gnomad.broadinstitute.org). ACMG/AMP criteria applied: BA1. -

Van der Woude syndrome 2

Benign:1

Jan 30, 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

0.21

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.56

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.30

.;T;.;.;.

Eigen

Benign

-0.32

Eigen_PC

Benign

-0.20

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.82

T;T;T;T;T

MetaRNN

Benign

0.0014

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.5

L;L;.;.;.

PhyloP100

0.46

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-2.3

N;N;N;D;N

REVEL

Benign

0.073

Sift

Benign

0.17

T;T;T;T;T

Sift4G

Benign

0.086

T;T;T;T;T

Polyphen

0.0030

.;.;.;.;B

Vest4

0.13

MutPred

0.44

Gain of disorder (P = 0.2314);Gain of disorder (P = 0.2314);.;.;.;

MPC

0.34

ClinPred

0.012

GERP RS

0.34

Varity_R

0.099

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