Genetic Variant STPG1:c.738-3184G>C (chr1-24364225-C-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_198174.3(GRHL3):c.1735C>G(p.Pro579Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000718 in 1,392,328 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. 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. P579S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

GRHL3
NM_198174.3 missense

Scores

Clinical Significance

Not reported in ClinVar

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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.039677262).

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>C		intron	N/A	NP_001185942.1	Q5TH74-1
GRHL3	NM_198174.3		c.1735C>G	p.Pro579Ala	missense	Exon 16 of 16	NP_937817.3
STPG1	NM_001199012.2		c.738-3184G>C		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>C		intron	N/A	ENSP00000337461.4	Q5TH74-1
STPG1	ENST00000468303.5	TSL:1	n.4211-3184G>C		intron	N/A
GRHL3	ENST00000350501.9	TSL:2	c.1735C>G	p.Pro579Ala	missense	Exon 16 of 16	ENSP00000288955.5	Q8TE85-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.18e-7

AC:

AN:

1392328

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

686418

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31328

American (AMR)

AF:

0.00

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:

0.00

AC:

AN:

5682

European-Non Finnish (NFE)

AF:

9.29e-7

AC:

AN:

1076498

Other (OTH)

AF:

0.00

AC:

AN:

57784

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.76

CADD

Benign

0.10

(source)

DANN

Benign

0.60

DEOGEN2

Benign

0.072

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.024

LIST_S2

Benign

0.31

M_CAP

Benign

0.00052

MetaRNN

Benign

0.040

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.0

PhyloP100

-0.46

PrimateAI

Benign

0.23

PROVEAN

Benign

0.88

REVEL

Benign

0.0090

Sift

Benign

0.81

Sift4G

Benign

0.53

Vest4

0.11

MutPred

0.25

Loss of catalytic residue at P578 (P = 0.0116)

MVP

0.068

MPC

0.35

ClinPred

0.046

GERP RS

-1.1

Varity_R

0.017

gMVP

0.15

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over