rs2486668

Variant names:

Variant summary

Our verdict is Benign. Variant got -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. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id 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

GnomAD3 exomes

AF:

0.158

AC:

39675

AN:

251202

Hom.:

3333

AF XY:

0.155

AC XY:

21071

AN XY:

135782

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 SAS exome

AF:

0.141

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

Gnomad4 AFR exome

AF:

0.197

Gnomad4 AMR exome

AF:

0.137

Gnomad4 ASJ exome

AF:

0.111

Gnomad4 EAS exome

AF:

0.164

Gnomad4 SAS exome

AF:

0.143

Gnomad4 FIN exome

AF:

0.154

Gnomad4 NFE exome

AF:

0.172

Gnomad4 OTH exome

AF:

0.167

GnomAD4 genome

AF:

0.170

AC:

25883

AN:

152120

Hom.:

2319

Cov.:

AF XY:

0.166

AC XY:

12371

AN XY:

74370

show subpopulations

Gnomad4 AFR

AF:

0.206

Gnomad4 AMR

AF:

0.126

Gnomad4 ASJ

AF:

0.107

Gnomad4 EAS

AF:

0.193

Gnomad4 SAS

AF:

0.148

Gnomad4 FIN

AF:

0.156

Gnomad4 NFE

AF:

0.165

Gnomad4 OTH

AF:

0.153

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

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;.;.;.

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over