dbSNP rs116396279: GRHL3:p.Asn484Ser (chr1-24344928-A-G) – ACMG Classification: Benign (-20 pts)

Variant summary

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

The NM_198174.3(GRHL3):c.1451A>G(p.Asn484Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0397 in 1,613,150 control chromosomes in the GnomAD database, including 1,470 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 (★★).

Frequency

Genomes: 𝑓 0.033 ( 104 hom., cov: 31)

Exomes 𝑓: 0.040 ( 1366 hom. )

Consequence

GRHL3
NM_198174.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.114

Publications

9 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=0.0019854307).

BP6

Variant 1-24344928-A-G is Benign according to our data. Variant chr1-24344928-A-G is described in ClinVar as Benign. ClinVar VariationId is 465249.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 = 0.0329 (4995/151784) while in subpopulation NFE AF = 0.0473 (3209/67866). AF 95% confidence interval is 0.0459. There are 104 homozygotes in GnomAd4. There are 2455 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High AC in GnomAd4 at 4995 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198174.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GRHL3	NM_198173.3	MANE Select	c.1451A>G	p.Asn484Ser	missense	Exon 12 of 16	NP_937816.1
GRHL3	NM_198174.3		c.1451A>G	p.Asn484Ser	missense	Exon 12 of 16	NP_937817.3
GRHL3	NM_021180.4		c.1466A>G	p.Asn489Ser	missense	Exon 12 of 16	NP_067003.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GRHL3	ENST00000361548.9	TSL:1 MANE Select	c.1451A>G	p.Asn484Ser	missense	Exon 12 of 16	ENSP00000354943.5
GRHL3	ENST00000236255.4	TSL:1	c.1466A>G	p.Asn489Ser	missense	Exon 12 of 16	ENSP00000236255.4
GRHL3	ENST00000356046.6	TSL:1	c.1313A>G	p.Asn438Ser	missense	Exon 12 of 16	ENSP00000348333.2

Frequencies

GnomAD3 genomes

AF:

0.0329

AC:

4992

AN:

151666

Hom.:

104

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00779

Gnomad AMI

AF:

0.00548

Gnomad AMR

AF:

0.0299

Gnomad ASJ

AF:

0.0294

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00892

Gnomad FIN

AF:

0.0738

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.0473

Gnomad OTH

AF:

0.0330

GnomAD2 exomes

AF:

0.0335

AC:

8420

AN:

251056

AF XY:

0.0334

show subpopulations

Gnomad AFR exome

AF:

0.00764

Gnomad AMR exome

AF:

0.0223

Gnomad ASJ exome

AF:

0.0367

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.0674

Gnomad NFE exome

AF:

0.0454

Gnomad OTH exome

AF:

0.0382

GnomAD4 exome

AF:

0.0404

AC:

59041

AN:

1461366

Hom.:

1366

Cov.:

AF XY:

0.0396

AC XY:

28823

AN XY:

727020

show subpopulations

African (AFR)

AF:

0.00627

AC:

210

AN:

33470

American (AMR)

AF:

0.0230

AC:

1027

AN:

44694

Ashkenazi Jewish (ASJ)

AF:

0.0357

AC:

931

AN:

26092

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39700

South Asian (SAS)

AF:

0.0108

AC:

929

AN:

86254

European-Finnish (FIN)

AF:

0.0717

AC:

3831

AN:

53394

Middle Eastern (MID)

AF:

0.0319

AC:

184

AN:

5760

European-Non Finnish (NFE)

AF:

0.0448

AC:

49769

AN:

1111632

Other (OTH)

AF:

0.0357

AC:

2158

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

2863

5726

8589

11452

14315

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1760

3520

5280

7040

8800

<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:

0.0329

AC:

4995

AN:

151784

Hom.:

104

Cov.:

AF XY:

0.0331

AC XY:

2455

AN XY:

74168

show subpopulations

African (AFR)

AF:

0.00777

AC:

321

AN:

41336

American (AMR)

AF:

0.0298

AC:

455

AN:

15254

Ashkenazi Jewish (ASJ)

AF:

0.0294

AC:

102

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00914

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.0738

AC:

778

AN:

10542

Middle Eastern (MID)

AF:

0.0408

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0473

AC:

3209

AN:

67866

Other (OTH)

AF:

0.0327

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

225

450

676

901

1126

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:

0.0391

Hom.:

240

Bravo

AF:

0.0287

TwinsUK

AF:

0.0502

AC:

186

ALSPAC

AF:

0.0490

AC:

189

ESP6500AA

AF:

0.00908

AC:

ESP6500EA

AF:

0.0460

AC:

396

ExAC

AF:

0.0324

AC:

3932

Asia WGS

AF:

0.00578

AC:

AN:

3476

EpiCase

AF:

0.0450

EpiControl

AF:

0.0442

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

GRHL3-related disorder (1)

Van der Woude syndrome 2 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.054

BayesDel_addAF

Benign

-0.74

BayesDel_noAF

Benign

-0.80

CADD

Benign

6.3

(source)

DANN

Benign

0.85

DEOGEN2

Benign

0.12

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.84

FATHMM_MKL

Benign

0.56

LIST_S2

Benign

0.73

MetaRNN

Benign

0.0020

MetaSVM

Benign

-0.90

MutationAssessor

Benign

1.0

PhyloP100

0.11

PrimateAI

Benign

0.38

PROVEAN

Benign

-0.030

REVEL

Benign

0.025

Sift

Benign

0.68

Sift4G

Benign

0.79

Polyphen

0.0010

Vest4

0.21

MPC

0.29

ClinPred

0.0011

GERP RS

-0.14

Varity_R

0.028

gMVP

0.16

Mutation Taster

=100/0

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over