1-24364225-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_198174.3(GRHL3):c.1735C>T(p.Pro579Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000427 in 1,544,672 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000036 ( 0 hom. )

Consequence

GRHL3
NM_198174.3 missense

Scores

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: -0.460

Publications

0 publications found

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 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

GRHL3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.031444103).

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.0000359 (50/1392328) while in subpopulation MID AF = 0.00088 (5/5682). AF 95% confidence interval is 0.000346. There are 0 homozygotes in GnomAdExome4. There are 22 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 16 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198174.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
STPG1	NM_001199013.2	MANE Select	c.738-3184G>A		intron	N/A	NP_001185942.1	Q5TH74-1
GRHL3	NM_198174.3		c.1735C>T	p.Pro579Ser	missense	Exon 16 of 16	NP_937817.3
STPG1	NM_001199012.2		c.738-3184G>A		intron	N/A	NP_001185941.1	Q5TH74-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
STPG1	ENST00000337248.9	TSL:5 MANE Select	c.738-3184G>A		intron	N/A	ENSP00000337461.4	Q5TH74-1
STPG1	ENST00000468303.5	TSL:1	n.4211-3184G>A		intron	N/A
GRHL3	ENST00000350501.9	TSL:2	c.1735C>T	p.Pro579Ser	missense	Exon 16 of 16	ENSP00000288955.5	Q8TE85-1

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000350

AC:

AN:

142780

AF XY:

0.0000260

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000441

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000747

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000359

AC:

AN:

1392328

Hom.:

Cov.:

AF XY:

0.0000321

AC XY:

AN XY:

686418

show subpopulations

African (AFR)

AF:

0.0000638

AC:

AN:

31328

American (AMR)

AF:

0.000115

AC:

AN:

34788

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25070

East Asian (EAS)

AF:

0.00

AC:

AN:

35124

South Asian (SAS)

AF:

0.00

AC:

AN:

77878

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48176

Middle Eastern (MID)

AF:

0.000880

AC:

AN:

5682

European-Non Finnish (NFE)

AF:

0.0000325

AC:

AN:

1076498

Other (OTH)

AF:

0.0000692

AC:

AN:

57784

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000105

AC:

AN:

152344

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74496

show subpopulations

African (AFR)

AF:

0.000168

AC:

AN:

41590

American (AMR)

AF:

0.000261

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.522

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000254

Hom.:

Bravo

AF:

0.000106

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

GRHL3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.70

CADD

Benign

0.23

(source)

DANN

Benign

0.79

DEOGEN2

Benign

0.072

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.026

LIST_S2

Benign

0.37

M_CAP

Benign

0.00060

MetaRNN

Benign

0.031

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.0

PhyloP100

-0.46

PrimateAI

Benign

0.23

PROVEAN

Benign

2.0

REVEL

Benign

0.073

Sift

Benign

0.081

Sift4G

Benign

0.44

Vest4

0.11

MutPred

0.16

Loss of catalytic residue at P579 (P = 0.0077)

MVP

0.068

MPC

0.37

ClinPred

0.036

GERP RS

-1.1

Varity_R

0.021

gMVP

0.23

Mutation Taster

=100/0

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over