rs41268753

Positions:

• chr1-24342967-C-T

Variant summary

Our verdict is Benign. Variant got -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:2
• Conservation: PhyloP100: 6.00

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=0.0035236776).
• BP6: Variant 1-24342967-C-T is Benign according to our data. Variant chr1-24342967-C-T is described in ClinVar as [Benign]. Clinvar id is 465245.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-24342967-C-T is described in Lovd as [Benign].
• 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 3402 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRHL3	NM_198173.3	c.1361C>T	p.Thr454Met	missense_variant	11/16	ENST00000361548.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRHL3	ENST00000361548.9	c.1361C>T	p.Thr454Met	missense_variant	11/16	1	NM_198173.3	P1

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

GnomAD3 exomes AF: 0.0228 AC: 5744 AN: 251466 Hom.: 103 AF XY: 0.0231 AC XY: 3143 AN XY: 135912

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 SAS exome AF: 0.00810

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

Gnomad4 AFR exome AF: 0.00517

Gnomad4 AMR exome AF: 0.0113

Gnomad4 ASJ exome AF: 0.00547

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00845

Gnomad4 FIN exome AF: 0.0525

Gnomad4 NFE exome AF: 0.0356

Gnomad4 OTH exome AF: 0.0270

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

Gnomad4 AFR AF: 0.00590

Gnomad4 AMR AF: 0.0129

Gnomad4 ASJ AF: 0.00374

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00916

Gnomad4 FIN AF: 0.0513

Gnomad4 NFE AF: 0.0337

Gnomad4 OTH AF: 0.0209

Alfa AF: 0.0290 Hom.: 124

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

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 04, 2021

This variant is associated with the following publications: (PMID: 27018475, 27018472, 28886269) -

Van der Woude syndrome 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

- -

Computational scores

Source: dbNSFP v4.3

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
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.98	D;D;D;D
MetaRNN	Benign	0.0035	T;T;T;T
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.6	M;M;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Benign	0.48	T
PROVEAN	Uncertain	-3.1	D;D;D;D
REVEL	Benign	0.18
Sift	Uncertain	0.0040	D;D;D;D
Sift4G	Uncertain	0.017	D;D;D;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

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: rs41268753; hg19: chr1-24669457;