rs2486668

Variant names:

• chr1-24331573-C-G
• rs2486668
• NM_198173.3:c.165C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2319 hom., cov: 32)
  • Exomes 𝑓: 0.17 (20866 hom.)
• Consequence: GRHL3 NM_198173.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.461
• Publications: 21 publications found

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 Gene-Disease associations (from GenCC):

• van der Woude syndrome 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• van der Woude syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198173.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRHL3	NM_198173.3	MANE Select	c.165C>G	p.Asp55Glu	missense	Exon 2 of 16	NP_937816.1	Q8TE85-5
	GRHL3	NM_198174.3		c.165C>G	p.Asp55Glu	missense	Exon 2 of 16	NP_937817.3
	GRHL3	NM_021180.4		c.180C>G	p.Asp60Glu	missense	Exon 2 of 16	NP_067003.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRHL3	ENST00000361548.9	TSL:1 MANE Select	c.165C>G	p.Asp55Glu	missense	Exon 2 of 16	ENSP00000354943.5	Q8TE85-5
	GRHL3	ENST00000236255.4	TSL:1	c.180C>G	p.Asp60Glu	missense	Exon 2 of 16	ENSP00000236255.4	Q8TE85-2
	GRHL3	ENST00000356046.6	TSL:1	c.27C>G	p.Asp9Glu	missense	Exon 2 of 16	ENSP00000348333.2	Q8TE85-3

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

GnomAD2 exomes AF: 0.158 AC: 39675 AN: 251202 AF XY: 0.155

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 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

African (AFR) AF: 0.197 AC: 6595 AN: 33472

American (AMR) AF: 0.137 AC: 6115 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.111 AC: 2899 AN: 26126

East Asian (EAS) AF: 0.164 AC: 6506 AN: 39696

South Asian (SAS) AF: 0.143 AC: 12332 AN: 86204

European-Finnish (FIN) AF: 0.154 AC: 8236 AN: 53418

Middle Eastern (MID) AF: 0.0624 AC: 360 AN: 5766

European-Non Finnish (NFE) AF: 0.172 AC: 190809 AN: 1111628

Other (OTH) AF: 0.167 AC: 10085 AN: 60382

GnomAD4 genome AF: 0.170 AC: 25883 AN: 152120 Hom.: 2319 Cov.: 32 AF XY: 0.166 AC XY: 12371 AN XY: 74370

African (AFR) AF: 0.206 AC: 8534 AN: 41478

American (AMR) AF: 0.126 AC: 1931 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.107 AC: 370 AN: 3468

East Asian (EAS) AF: 0.193 AC: 997 AN: 5162

South Asian (SAS) AF: 0.148 AC: 714 AN: 4822

European-Finnish (FIN) AF: 0.156 AC: 1654 AN: 10594

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.165 AC: 11208 AN: 67990

Other (OTH) AF: 0.153 AC: 323 AN: 2116

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)
-	-	1	Van der Woude syndrome 2 (1)

Computational scores

Source: dbNSFP v4.9

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
MetaRNN	Benign	0.0014	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L
PhyloP100		0.46
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.073
Sift	Benign	0.17	T
Sift4G	Benign	0.086	T
Polyphen		0.0030	B
Vest4		0.13
MutPred		0.44		Gain of disorder (P = 0.2314)
MPC		0.34
ClinPred		0.012	T
GERP RS		0.34
Varity_R		0.099
gMVP		0.36
Mutation Taster		=96/4	polymorphism (auto)

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

Other links and lift over

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