chr1-24331440-G-A

Position:

chr1-24331440-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_198173.3(GRHL3):c.32G>A(p.Arg11Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000215 in 1,612,412 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00081 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

GRHL3
NM_198173.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter P:1U:1B:1

Conservation

PhyloP100: 2.15

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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009678006).

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000808 (123/152264) while in subpopulation AFR AF= 0.00241 (100/41546). AF 95% confidence interval is 0.00202. There are 0 homozygotes in gnomad4. There are 66 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 123 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GRHL3	NM_198173.3 linkuse as main transcript	c.32G>A	p.Arg11Gln	missense_variant	2/16	ENST00000361548.9	NP_937816.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GRHL3	ENST00000361548.9 linkuse as main transcript	c.32G>A	p.Arg11Gln	missense_variant	2/16	1	NM_198173.3	ENSP00000354943	P1	Q8TE85-5

Frequencies

GnomAD3 genomes

AF:

0.000802

AC:

122

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00239

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000589

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000962

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000566

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000957

GnomAD3 exomes

AF:

0.000360

AC:

AN:

249946

Hom.:

AF XY:

0.000259

AC XY:

AN XY:

135082

show subpopulations

Gnomad AFR exome

AF:

0.00326

Gnomad AMR exome

AF:

0.000236

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000817

Gnomad SAS exome

AF:

0.000132

Gnomad FIN exome

AF:

0.000278

Gnomad NFE exome

AF:

0.0000265

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.000153

AC:

224

AN:

1460148

Hom.:

Cov.:

AF XY:

0.000128

AC XY:

AN XY:

726352

show subpopulations

Gnomad4 AFR exome

AF:

0.00326

Gnomad4 AMR exome

AF:

0.000292

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000706

Gnomad4 SAS exome

AF:

0.000198

Gnomad4 FIN exome

AF:

0.000356

Gnomad4 NFE exome

AF:

0.0000189

Gnomad4 OTH exome

AF:

0.000282

GnomAD4 genome

AF:

0.000808

AC:

123

AN:

152264

Hom.:

Cov.:

AF XY:

0.000887

AC XY:

AN XY:

74444

show subpopulations

Gnomad4 AFR

AF:

0.00241

Gnomad4 AMR

AF:

0.000588

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000965

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000566

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000947

Alfa

AF:

0.000212

Hom.:

Bravo

AF:

0.000880

ESP6500AA

AF:

0.00272

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000420

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000594

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:1Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Isolated cleft palate

Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

Orthodontics Department, Peking University School and Hospital of Stomatology

Mar 01, 2021

- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 11, 2021

The c.32G>A (p.R11Q) alteration is located in exon 2 (coding exon 2) of the GRHL3 gene. This alteration results from a G to A substitution at nucleotide position 32, causing the arginine (R) at amino acid position 11 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

GRHL3-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 20, 2019

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

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.094

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.53

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.086

.;T;.

Eigen

Benign

-0.039

Eigen_PC

Benign

0.18

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.75

T;T;D

M_CAP

Benign

0.0051

MetaRNN

Benign

0.0097

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.92

L;L;.

MutationTaster

Benign

1.0

D;D;N;N;N

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-0.32

N;N;N

REVEL

Benign

0.058

Sift

Benign

0.24

T;T;T

Sift4G

Benign

0.53

T;T;T

Polyphen

0.055

.;.;B

Vest4

0.26

MVP

0.082

MPC

0.42

ClinPred

0.018

GERP RS

5.0

Varity_R

0.067

gMVP

0.38

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

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