1-24364186-G-A

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_198174.3(GRHL3):c.1696G>A(p.Glu566Lys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0405 in 1,489,000 control chromosomes in the GnomAD database, including 1,419 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.030 ( 98 hom., cov: 33)

Exomes 𝑓: 0.042 ( 1321 hom. )

Consequence

GRHL3
NM_198174.3 missense, splice_region

Scores

Splicing: ADA: 0.004821

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.0520

Variant links:

Genes affected

STPG1 (HGNC:28070): (sperm tail PG-rich repeat containing 1) Involved in positive regulation of apoptotic process and positive regulation of mitochondrial membrane permeability involved in apoptotic process. Predicted to be located in mitochondrion and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

STPG1 links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0029179454).

BP6

Variant 1-24364186-G-A is Benign according to our data. Variant chr1-24364186-G-A is described in ClinVar as [Benign]. Clinvar id is 218865.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-24364186-G-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0303 (4619/152264) while in subpopulation NFE AF= 0.0472 (3214/68030). AF 95% confidence interval is 0.0459. There are 98 homozygotes in gnomad4. There are 2185 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 4619 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STPG1	NM_001199013.2 link	c.738-3145C>T		intron_variant	Intron 7 of 8	ENST00000337248.9	NP_001185942.1	Q5TH74-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STPG1	ENST00000337248.9 link	c.738-3145C>T		intron_variant	Intron 7 of 8	5	NM_001199013.2	ENSP00000337461.4		Q5TH74-1

Frequencies

GnomAD3 genomes

AF:

0.0304

AC:

4625

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00727

Gnomad AMI

AF:

0.0318

Gnomad AMR

AF:

0.0252

Gnomad ASJ

AF:

0.0435

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00932

Gnomad FIN

AF:

0.0395

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.0473

Gnomad OTH

AF:

0.0335

GnomAD3 exomes

AF:

0.0322

AC:

3301

AN:

102552

Hom.:

AF XY:

0.0319

AC XY:

1771

AN XY:

55480

show subpopulations

Gnomad AFR exome

AF:

0.00550

Gnomad AMR exome

AF:

0.0236

Gnomad ASJ exome

AF:

0.0443

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00842

Gnomad FIN exome

AF:

0.0383

Gnomad NFE exome

AF:

0.0470

Gnomad OTH exome

AF:

0.0422

GnomAD4 exome

AF:

0.0417

AC:

55679

AN:

1336736

Hom.:

1321

Cov.:

AF XY:

0.0409

AC XY:

26767

AN XY:

654368

show subpopulations

Gnomad4 AFR exome

AF:

0.00732

Gnomad4 AMR exome

AF:

0.0206

Gnomad4 ASJ exome

AF:

0.0452

Gnomad4 EAS exome

AF:

0.0000300

Gnomad4 SAS exome

AF:

0.0102

Gnomad4 FIN exome

AF:

0.0390

Gnomad4 NFE exome

AF:

0.0469

Gnomad4 OTH exome

AF:

0.0359

GnomAD4 genome

AF:

0.0303

AC:

4619

AN:

152264

Hom.:

Cov.:

AF XY:

0.0293

AC XY:

2185

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.00725

Gnomad4 AMR

AF:

0.0251

Gnomad4 ASJ

AF:

0.0435

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00932

Gnomad4 FIN

AF:

0.0395

Gnomad4 NFE

AF:

0.0472

Gnomad4 OTH

AF:

0.0327

Alfa

AF:

0.0412

Hom.:

202

Bravo

AF:

0.0294

TwinsUK

AF:

0.0456

AC:

169

ALSPAC

AF:

0.0405

AC:

156

ExAC

AF:

0.0218

AC:

480

Asia WGS

AF:

0.00520

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Dec 31, 2014

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

GRHL3-related disorder

Benign:1

Jun 11, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Van der Woude syndrome 2

Benign:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.56

CADD

Benign

4.6

DANN

Uncertain

0.98

DEOGEN2

Benign

0.13

Eigen

Benign

-0.35

Eigen_PC

Benign

-0.53

FATHMM_MKL

Benign

0.042

LIST_S2

Benign

0.42

MetaRNN

Benign

0.0029

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.0

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.020

REVEL

Benign

0.080

Sift

Uncertain

0.010

Sift4G

Uncertain

0.0050

Vest4

0.052

MPC

0.62

ClinPred

0.0044

GERP RS

1.9

Varity_R

0.038

gMVP

0.65

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0048

dbscSNV1_RF

Benign

0.032

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over