1-24364202-A-C

Variant names:

• chr1-24364202-A-C
• rs1050497646
• NM_001199013.2:c.738-3161T>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_198174.3(GRHL3):​c.1712A>C​(p.His571Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. H571L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GRHL3 NM_198174.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.163
• Publications: 0 publications found

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]

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

ACMG classification

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=0.0743632).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STPG1	NM_001199013.2	MANE Select	c.738-3161T>G		intron	N/A	NP_001185942.1	Q5TH74-1
	GRHL3	NM_198174.3		c.1712A>C	p.His571Pro	missense	Exon 16 of 16	NP_937817.3
	STPG1	NM_001199012.2		c.738-3161T>G		intron	N/A	NP_001185941.1	Q5TH74-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STPG1	ENST00000337248.9	TSL:5 MANE Select	c.738-3161T>G		intron	N/A	ENSP00000337461.4	Q5TH74-1
	STPG1	ENST00000468303.5	TSL:1	n.4211-3161T>G		intron	N/A
	GRHL3	ENST00000350501.9	TSL:2	c.1712A>C	p.His571Pro	missense	Exon 16 of 16	ENSP00000288955.5	Q8TE85-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	2.1
DANN	Benign	0.50
DEOGEN2	Benign	0.14	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0066	N
LIST_S2	Benign	0.32	T
M_CAP	Benign	0.0014	T
MetaRNN	Benign	0.074	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.16
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.070	N
REVEL	Benign	0.023
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.0060	D
Vest4		0.10
MutPred		0.43		Gain of catalytic residue at H571 (P = 0.0451)
MVP		0.043
MPC		0.75
ClinPred		0.052	T
GERP RS		-7.0
Varity_R		0.056
gMVP		0.53
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs1050497646; hg19: chr1-24690692;