rs34637004

Variant names:

Your query was ambiguous. Multiple possible variants found:

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.479T>C(p.Val160Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0392 in 1,614,096 control chromosomes in the GnomAD database, including 1,490 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V160G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.034 ( 119 hom., cov: 32)

Exomes 𝑓: 0.040 ( 1371 hom. )

Consequence

GRHL3
NM_198173.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.288

Publications

13 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=0.0018627644).

BP6

Variant 1-24336694-T-C is Benign according to our data. Variant chr1-24336694-T-C is described in ClinVar as Benign. ClinVar VariationId is 465250.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 = 0.0335 (5104/152286) while in subpopulation NFE AF = 0.0462 (3143/68016). AF 95% confidence interval is 0.0449. There are 119 homozygotes in GnomAd4. There are 2573 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 5104 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRHL3	NM_198173.3 link	c.479T>C	p.Val160Ala	missense_variant	Exon 4 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.479T>C	p.Val160Ala	missense_variant	Exon 4 of 16	1	NM_198173.3	ENSP00000354943.5		Q8TE85-5

Frequencies

GnomAD3 genomes

AF:

0.0335

AC:

5101

AN:

152168

Hom.:

119

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00755

Gnomad AMI

AF:

0.00548

Gnomad AMR

AF:

0.0286

Gnomad ASJ

AF:

0.0314

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0101

Gnomad FIN

AF:

0.0912

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.0462

Gnomad OTH

AF:

0.0320

GnomAD2 exomes

AF:

0.0339

AC:

8531

AN:

251324

AF XY:

0.0339

show subpopulations

Gnomad AFR exome

AF:

0.00696

Gnomad AMR exome

AF:

0.0204

Gnomad ASJ exome

AF:

0.0388

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.0790

Gnomad NFE exome

AF:

0.0446

Gnomad OTH exome

AF:

0.0373

GnomAD4 exome

AF:

0.0398

AC:

58159

AN:

1461810

Hom.:

1371

Cov.:

AF XY:

0.0391

AC XY:

28400

AN XY:

727212

show subpopulations

African (AFR)

AF:

0.00597

AC:

200

AN:

33480

American (AMR)

AF:

0.0212

AC:

949

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.0385

AC:

1007

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.0106

AC:

910

AN:

86252

European-Finnish (FIN)

AF:

0.0841

AC:

4489

AN:

53394

Middle Eastern (MID)

AF:

0.0309

AC:

178

AN:

5768

European-Non Finnish (NFE)

AF:

0.0435

AC:

48322

AN:

1111976

Other (OTH)

AF:

0.0348

AC:

2103

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

3029

6058

9086

12115

15144

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1700

3400

5100

6800

8500

<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:

0.0335

AC:

5104

AN:

152286

Hom.:

119

Cov.:

AF XY:

0.0346

AC XY:

2573

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.00753

AC:

313

AN:

41570

American (AMR)

AF:

0.0286

AC:

437

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0314

AC:

109

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.0104

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0912

AC:

968

AN:

10612

Middle Eastern (MID)

AF:

0.0408

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0462

AC:

3143

AN:

68016

Other (OTH)

AF:

0.0317

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

245

491

736

982

1227

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

168

224

280

<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:

0.0385

Hom.:

309

Bravo

AF:

0.0280

TwinsUK

AF:

0.0499

AC:

185

ALSPAC

AF:

0.0480

AC:

185

ESP6500AA

AF:

0.00862

AC:

ESP6500EA

AF:

0.0450

AC:

387

ExAC

AF:

0.0327

AC:

3970

Asia WGS

AF:

0.00577

AC:

AN:

3478

EpiCase

AF:

0.0449

EpiControl

AF:

0.0439

ClinVar

Significance: Benign

Submissions summary: Benign:4

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

- -

GRHL3-related disorder

Benign:1

Mar 20, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Van der Woude syndrome 2

Benign:1

Jan 24, 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

0.065

BayesDel_addAF

Benign

-0.74

BayesDel_noAF

Benign

-0.80

CADD

Benign

(source)

DANN

Benign

0.82

DEOGEN2

Benign

0.070

.;T;.;.

Eigen

Benign

-0.45

Eigen_PC

Benign

-0.23

FATHMM_MKL

Benign

0.63

LIST_S2

Benign

0.56

T;T;T;T

MetaRNN

Benign

0.0019

T;T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-0.55

N;N;.;.

PhyloP100

0.29

PrimateAI

Benign

0.44

PROVEAN

Benign

0.70

N;N;N;N

REVEL

Benign

0.043

Sift

Benign

0.51

T;T;T;T

Sift4G

Benign

0.52

T;T;T;T

Polyphen

0.0

.;.;.;B

Vest4

0.21

MPC

0.44

ClinPred

0.0049

GERP RS

3.7

Varity_R

0.053

gMVP

0.22

Mutation Taster

=99/1

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