chr1-24342967-C-T

Variant names:

• chr1-24342967-C-T
• rs41268753
• NM_198173.3:c.1361C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_198173.3(GRHL3):​c.1361C>T​(p.Thr454Met) variant causes a missense change. The variant allele was found at a frequency of 0.0304 in 1,614,014 control chromosomes in the GnomAD database, including 967 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (55 hom., cov: 32)
  • Exomes 𝑓: 0.031 (912 hom.)
• Consequence: GRHL3 NM_198173.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 6.00
• Publications: 45 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=0.0035236776).
• BP6: Variant 1-24342967-C-T is Benign according to our data. Variant chr1-24342967-C-T is described in ClinVar as Benign. ClinVar VariationId is 465245.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0224 (3402/152148) while in subpopulation NFE AF = 0.0337 (2290/67998). AF 95% confidence interval is 0.0325. There are 55 homozygotes in GnomAd4. There are 1686 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 3402 AD gene.

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.1361C>T	p.Thr454Met	missense	Exon 11 of 16	NP_937816.1	Q8TE85-5
	GRHL3	NM_198174.3		c.1361C>T	p.Thr454Met	missense	Exon 11 of 16	NP_937817.3
	GRHL3	NM_021180.4		c.1376C>T	p.Thr459Met	missense	Exon 11 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.1361C>T	p.Thr454Met	missense	Exon 11 of 16	ENSP00000354943.5	Q8TE85-5
	GRHL3	ENST00000236255.4	TSL:1	c.1376C>T	p.Thr459Met	missense	Exon 11 of 16	ENSP00000236255.4	Q8TE85-2
	GRHL3	ENST00000356046.6	TSL:1	c.1223C>T	p.Thr408Met	missense	Exon 11 of 16	ENSP00000348333.2	Q8TE85-3

Frequencies

GnomAD3 genomes AF: 0.0224 AC: 3403 AN: 152030 Hom.: 56 Cov.: 32

Gnomad AFR AF: 0.00590

Gnomad AMI AF: 0.0209

Gnomad AMR AF: 0.0130

Gnomad ASJ AF: 0.00374

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00957

Gnomad FIN AF: 0.0513

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0337

Gnomad OTH AF: 0.0211

GnomAD2 exomes AF: 0.0228 AC: 5744 AN: 251466 AF XY: 0.0231

Gnomad AFR exome AF: 0.00597

Gnomad AMR exome AF: 0.0107

Gnomad ASJ exome AF: 0.00615

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.0540

Gnomad NFE exome AF: 0.0321

Gnomad OTH exome AF: 0.0236

GnomAD4 exome AF: 0.0313 AC: 45693 AN: 1461866 Hom.: 912 Cov.: 32 AF XY: 0.0309 AC XY: 22497 AN XY: 727238

African (AFR) AF: 0.00517 AC: 173 AN: 33480

American (AMR) AF: 0.0113 AC: 505 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00547 AC: 143 AN: 26136

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39700

South Asian (SAS) AF: 0.00845 AC: 729 AN: 86256

European-Finnish (FIN) AF: 0.0525 AC: 2805 AN: 53416

Middle Eastern (MID) AF: 0.0179 AC: 103 AN: 5768

European-Non Finnish (NFE) AF: 0.0356 AC: 39603 AN: 1111990

Other (OTH) AF: 0.0270 AC: 1629 AN: 60396

GnomAD4 genome AF: 0.0224 AC: 3402 AN: 152148 Hom.: 55 Cov.: 32 AF XY: 0.0227 AC XY: 1686 AN XY: 74374

African (AFR) AF: 0.00590 AC: 245 AN: 41506

American (AMR) AF: 0.0129 AC: 198 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00374 AC: 13 AN: 3472

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5158

South Asian (SAS) AF: 0.00916 AC: 44 AN: 4804

European-Finnish (FIN) AF: 0.0513 AC: 544 AN: 10602

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0337 AC: 2290 AN: 67998

Other (OTH) AF: 0.0209 AC: 44 AN: 2110

Alfa AF: 0.0285 Hom.: 264

Bravo AF: 0.0194

TwinsUK AF: 0.0343 AC: 127

ALSPAC AF: 0.0394 AC: 152

ESP6500AA AF: 0.00613 AC: 27

ESP6500EA AF: 0.0317 AC: 273

ExAC AF: 0.0228 AC: 2765

Asia WGS AF: 0.00260 AC: 9 AN: 3476

EpiCase AF: 0.0293

EpiControl AF: 0.0292

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.43
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.70	D
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.98	D
MetaRNN	Benign	0.0035	T
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		6.0
PrimateAI	Benign	0.48	T
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.18
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.017	D
Polyphen		1.0	D
Vest4		0.34
MPC		1.1
ClinPred		0.0095	T
GERP RS		4.3
Varity_R		0.28
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: rs41268753; hg19: chr1-24669457; COSMIC: COSV107246498;