Genetic Variant STPG1:c.738-3233A>G (chr1-24364274-T-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_198174.3(GRHL3):c.1784T>C(p.Met595Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000716 in 1,396,832 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M595K) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

GRHL3
NM_198174.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.294

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.11212134).

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.738-3233A>G		intron	N/A	NP_001185942.1	Q5TH74-1
GRHL3	NM_198174.3		c.1784T>C	p.Met595Thr	missense	Exon 16 of 16	NP_937817.3
STPG1	NM_001199012.2		c.738-3233A>G		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.738-3233A>G		intron	N/A	ENSP00000337461.4	Q5TH74-1
STPG1	ENST00000468303.5	TSL:1	n.4211-3233A>G		intron	N/A
GRHL3	ENST00000350501.9	TSL:2	c.1784T>C	p.Met595Thr	missense	Exon 16 of 16	ENSP00000288955.5	Q8TE85-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.16e-7

AC:

AN:

1396832

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

688892

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31544

American (AMR)

AF:

0.00

AC:

AN:

35492

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25168

East Asian (EAS)

AF:

0.00

AC:

AN:

35550

South Asian (SAS)

AF:

0.0000127

AC:

AN:

78792

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48164

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5694

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1078496

Other (OTH)

AF:

0.00

AC:

AN:

57932

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.675

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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.63

CADD

Benign

3.4

(source)

DANN

Benign

0.75

DEOGEN2

Benign

0.24

Eigen

Benign

-0.69

Eigen_PC

Benign

-0.86

FATHMM_MKL

Benign

0.021

LIST_S2

Benign

0.26

M_CAP

Benign

0.0012

MetaRNN

Benign

0.11

MetaSVM

Benign

-0.98

MutationAssessor

Uncertain

2.2

PhyloP100

-0.29

PrimateAI

Benign

0.32

PROVEAN

Benign

-2.1

REVEL

Benign

0.028

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Vest4

0.13

MutPred

0.29

Loss of stability (P = 0.0646)

MVP

0.043

MPC

0.45

ClinPred

0.33

GERP RS

-1.2

Varity_R

0.51

gMVP

0.27

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over