rs2486668

Positions:

• chr1-24331573-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000361548.9(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 same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.17 (2319 hom., cov: 32)
  • Exomes 𝑓: 0.17 (20866 hom.)
• Consequence: GRHL3 ENST00000361548.9 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.461

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]

ACMG classification

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/exons	MANE	Protein	UniProt
GRHL3	NM_198173.3	c.165C>G	p.Asp55Glu	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	c.165C>G	p.Asp55Glu	missense_variant	2/16	1	NM_198173.3	ENSP00000354943	P1

Frequencies

GnomAD3 genomes AF: 0.170 AC: 25869 AN: 152002 Hom.: 2314 Cov.: 32

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

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.: 32 AF XY: 0.165 AC XY: 120267 AN XY: 727028

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.: 32 AF XY: 0.166 AC XY: 12371 AN XY: 74370

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

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 18, 2020	This variant is associated with the following publications: (PMID: 31332962) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 08, 2021

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.30	.;T;.;.;.
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.20
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.82	T;T;T;T;T
MetaRNN	Benign	0.0014	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L;L;.;.;.
MutationTaster	Benign	0.059	P;P;P;P;P
PrimateAI	Uncertain	0.68	T
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	T
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

Other links and lift over

dbSNP: rs2486668; hg19: chr1-24658063; COSMIC: COSV52565223;