Genetic Variant NM_198173.3:c.893G>A (chr1-24338044-G-A) – ACMG Classification: Likely_benign (-3 pts)

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP5BS2

The NM_198173.3(GRHL3):c.893G>A(p.Arg298His) variant causes a missense change. The variant allele was found at a frequency of 0.0000186 in 1,613,070 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R298C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000020 ( 0 hom. )

Consequence

GRHL3
NM_198173.3 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 6.35

Publications

3 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: Likely_benign. The variant received -3 ACMG points.

PP5

Variant 1-24338044-G-A is Pathogenic according to our data. Variant chr1-24338044-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 101518.Status of the report is no_assertion_criteria_provided, 0 stars.

BS2

High AC in GnomAdExome4 at 29 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRHL3	NM_198173.3 link	c.893G>A	p.Arg298His	missense_variant	Exon 7 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.893G>A	p.Arg298His	missense_variant	Exon 7 of 16	1	NM_198173.3	ENSP00000354943.5		Q8TE85-5

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000200

AC:

AN:

250372

AF XY:

0.0000296

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:

0.00

Gnomad NFE exome

AF:

0.00000883

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000199

AC:

AN:

1460886

Hom.:

Cov.:

AF XY:

0.0000261

AC XY:

AN XY:

726736

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33432

American (AMR)

AF:

0.00

AC:

AN:

44510

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26104

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.000209

AC:

AN:

86096

European-Finnish (FIN)

AF:

0.000112

AC:

AN:

53390

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00000360

AC:

AN:

1111554

Other (OTH)

AF:

0.0000166

AC:

AN:

60340

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152184

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74338

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41434

American (AMR)

AF:

0.00

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.000207

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68036

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000407

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Van der Woude syndrome 2

Pathogenic:1

Jan 02, 2014

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.36

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.73

.;D;.;.

Eigen

Pathogenic

0.78

Eigen_PC

Pathogenic

0.79

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.96

D;D;D;D

M_CAP

Benign

0.015

MetaRNN

Uncertain

0.65

D;D;D;D

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.8

L;L;.;.

PhyloP100

6.3

PrimateAI

Uncertain

0.55

PROVEAN

Uncertain

-3.4

D;D;D;D

REVEL

Pathogenic

0.73

Sift

Uncertain

0.0020

D;D;D;D

Sift4G

Uncertain

0.0040

D;D;D;D

Polyphen

1.0

.;.;.;D

Vest4

0.61

MutPred

0.59

Loss of MoRF binding (P = 0.0083);Loss of MoRF binding (P = 0.0083);.;.;

MVP

0.26

MPC

1.2

ClinPred

0.89

GERP RS

6.1

Varity_R

0.60

gMVP

0.46

Mutation Taster

=3/97

disease causing (ClinVar)

(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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NM_198173.3:c.893G>A

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