1-24331440-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

3
16

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]

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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 UniProt
GRHL3NM_198173.3 linkuse as main transcriptc.32G>A p.Arg11Gln missense_variant 2/16 ENST00000361548.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
GRHL3ENST00000361548.9 linkuse as main transcriptc.32G>A p.Arg11Gln missense_variant 2/161 NM_198173.3 P1Q8TE85-5

Frequencies

GnomAD3 genomes
AF:
0.000802
AC:
122
AN:
152146
Hom.:
0
Cov.:
32
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:
90
AN:
249946
Hom.:
0
AF XY:
0.000259
AC XY:
35
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.:
0
Cov.:
31
AF XY:
0.000128
AC XY:
93
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.:
0
Cov.:
32
AF XY:
0.000887
AC XY:
66
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.:
0
Bravo
AF:
0.000880
ESP6500AA
AF:
0.00272
AC:
12
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.000420
AC:
51
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 providedresearchOrthodontics Department, Peking University School and Hospital of StomatologyMar 01, 2021- -
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJun 11, 2021The 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 providedclinical testingPreventionGenetics, part of Exact SciencesNov 20, 2019This 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
T
BayesDel_noAF
Benign
-0.53
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Benign
0.086
.;T;.
Eigen
Benign
-0.039
Eigen_PC
Benign
0.18
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Benign
0.75
T;T;D
M_CAP
Benign
0.0051
T
MetaRNN
Benign
0.0097
T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.92
L;L;.
MutationTaster
Benign
1.0
D;D;N;N;N
PrimateAI
Uncertain
0.52
T
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
T
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.

Other links and lift over

dbSNP: rs142248927; hg19: chr1-24657930; COSMIC: COSV52567136; API