Variant rs770938921 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP3PP5BS2

The NM_198173.3(GRHL3):c.1225C>T(p.Arg409Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,828 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. R409R) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

GRHL3
NM_198173.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1

Conservation

PhyloP100: 0.0410

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 Likely_benign. Variant got -2 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.751

PP5

Variant 1-24342712-C-T is Pathogenic according to our data. Variant chr1-24342712-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 496682.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.

BS2

High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GRHL3	NM_198173.3 linkuse as main transcript	c.1225C>T	p.Arg409Cys	missense_variant	10/16	ENST00000361548.9	NP_937816.1	Q8TE85-5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GRHL3	ENST00000361548.9 linkuse as main transcript	c.1225C>T	p.Arg409Cys	missense_variant	10/16	1	NM_198173.3	ENSP00000354943.5		Q8TE85-5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000239

AC:

AN:

251398

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135902

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461828

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727226

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Van der Woude syndrome 1

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Feb 15, 2017

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jun 14, 2022

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Uncertain

0.055

BayesDel_noAF

Uncertain

0.020

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.85

.;D;.;.

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Uncertain

0.94

LIST_S2

Pathogenic

0.99

D;D;D;D

M_CAP

Benign

0.039

MetaRNN

Pathogenic

0.75

D;D;D;D

MetaSVM

Benign

-0.92

MutationAssessor

Uncertain

2.8

M;M;.;.

PrimateAI

Uncertain

0.79

PROVEAN

Pathogenic

-7.4

D;D;D;D

REVEL

Benign

0.27

Sift

Uncertain

0.0010

D;D;D;D

Sift4G

Uncertain

0.0020

D;D;D;D

Polyphen

1.0

.;.;.;D

Vest4

0.82

MutPred

0.63

Loss of MoRF binding (P = 0.0067);Loss of MoRF binding (P = 0.0067);.;.;

MVP

0.39

MPC

1.4

ClinPred

1.0

GERP RS

5.0

Varity_R

0.91

gMVP

0.48

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