chr1-24364186-G-T

Variant names:

• chr1-24364186-G-T
• rs6694170
• NM_001199013.2:c.738-3145C>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The NM_198174.3(GRHL3):​c.1696G>T​(p.Glu566*) variant causes a stop gained, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000224 in 1,336,810 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: GRHL3 NM_198174.3 stop_gained, splice_region
• Scores: Splicing: ADA: 0.4324
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0520
• Publications: 6 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 4 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0984 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

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.738-3145C>A		intron	N/A	NP_001185942.1	Q5TH74-1
	GRHL3	NM_198174.3		c.1696G>T	p.Glu566*	stop_gained splice_region	Exon 16 of 16	NP_937817.3
	STPG1	NM_001199012.2		c.738-3145C>A		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.738-3145C>A		intron	N/A	ENSP00000337461.4	Q5TH74-1
	STPG1	ENST00000468303.5	TSL:1	n.4211-3145C>A		intron	N/A
	GRHL3	ENST00000350501.9	TSL:2	c.1696G>T	p.Glu566*	stop_gained splice_region	Exon 16 of 16	ENSP00000288955.5	Q8TE85-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000195 AC: 2 AN: 102552 AF XY: 0.0000360

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000490

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000224 AC: 3 AN: 1336810 Hom.: 0 Cov.: 30 AF XY: 0.00000458 AC XY: 3 AN XY: 654414

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 28840

American (AMR) AF: 0.00 AC: 0 AN: 24074

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22574

East Asian (EAS) AF: 0.00 AC: 0 AN: 33368

South Asian (SAS) AF: 0.00 AC: 0 AN: 70082

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47230

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5450

European-Non Finnish (NFE) AF: 0.00000286 AC: 3 AN: 1049846

Other (OTH) AF: 0.00 AC: 0 AN: 55346

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0136242), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 488

ExAC AF: 0.0000455 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	34
DANN	Uncertain	0.98
Eigen	Uncertain	0.23
Eigen_PC	Benign	-0.17
FATHMM_MKL	Benign	0.037	N
PhyloP100		-0.052
Vest4		0.46
GERP RS		1.9
Mutation Taster		=129/71	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.43
dbscSNV1_RF	Benign	0.62
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: rs6694170; hg19: chr1-24690676;