NM_001199013.2:c.738-3233A>T

Variant names:

• chr1-24364274-T-A
• rs545809
• NM_001199013.2:c.738-3233A>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001199013.2(STPG1):​c.738-3233A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.271 in 1,548,420 control chromosomes in the GnomAD database, including 58,230 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (5291 hom., cov: 32)
  • Exomes 𝑓: 0.27 (52939 hom.)
• Consequence: STPG1 NM_001199013.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.294
• Publications: 19 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016256869).
• BP6: Variant 1-24364274-T-A is Benign according to our data. Variant chr1-24364274-T-A is described in ClinVar as Benign. ClinVar VariationId is 1164479.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.388 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001199013.2. 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.738-3233A>T		intron	N/A	NP_001185942.1	Q5TH74-1
	GRHL3	NM_198174.3		c.1784T>A	p.Met595Lys	missense	Exon 16 of 16	NP_937817.3
	STPG1	NM_001199012.2		c.738-3233A>T		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.738-3233A>T		intron	N/A	ENSP00000337461.4	Q5TH74-1
	STPG1	ENST00000468303.5	TSL:1	n.4211-3233A>T		intron	N/A
	GRHL3	ENST00000350501.9	TSL:2	c.1784T>A	p.Met595Lys	missense	Exon 16 of 16	ENSP00000288955.5	Q8TE85-1

Frequencies

GnomAD3 genomes AF: 0.261 AC: 39679 AN: 151960 Hom.: 5281 Cov.: 32

Gnomad AFR AF: 0.226

Gnomad AMI AF: 0.239

Gnomad AMR AF: 0.256

Gnomad ASJ AF: 0.308

Gnomad EAS AF: 0.401

Gnomad SAS AF: 0.367

Gnomad FIN AF: 0.225

Gnomad MID AF: 0.329

Gnomad NFE AF: 0.268

Gnomad OTH AF: 0.299

GnomAD2 exomes AF: 0.292 AC: 42937 AN: 147140 AF XY: 0.298

Gnomad AFR exome AF: 0.216

Gnomad AMR exome AF: 0.291

Gnomad ASJ exome AF: 0.301

Gnomad EAS exome AF: 0.413

Gnomad FIN exome AF: 0.223

Gnomad NFE exome AF: 0.269

Gnomad OTH exome AF: 0.280

GnomAD4 exome AF: 0.272 AC: 379220 AN: 1396342 Hom.: 52939 Cov.: 33 AF XY: 0.275 AC XY: 189187 AN XY: 688648

African (AFR) AF: 0.224 AC: 7050 AN: 31532

American (AMR) AF: 0.288 AC: 10199 AN: 35446

Ashkenazi Jewish (ASJ) AF: 0.303 AC: 7625 AN: 25152

East Asian (EAS) AF: 0.413 AC: 14688 AN: 35524

South Asian (SAS) AF: 0.368 AC: 28984 AN: 78684

European-Finnish (FIN) AF: 0.221 AC: 10651 AN: 48150

Middle Eastern (MID) AF: 0.358 AC: 2041 AN: 5694

European-Non Finnish (NFE) AF: 0.261 AC: 281889 AN: 1078256

Other (OTH) AF: 0.278 AC: 16093 AN: 57904

GnomAD4 genome AF: 0.261 AC: 39725 AN: 152078 Hom.: 5291 Cov.: 32 AF XY: 0.263 AC XY: 19519 AN XY: 74348

African (AFR) AF: 0.226 AC: 9377 AN: 41486

American (AMR) AF: 0.256 AC: 3912 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.308 AC: 1070 AN: 3470

East Asian (EAS) AF: 0.402 AC: 2069 AN: 5144

South Asian (SAS) AF: 0.367 AC: 1768 AN: 4814

European-Finnish (FIN) AF: 0.225 AC: 2377 AN: 10584

Middle Eastern (MID) AF: 0.316 AC: 93 AN: 294

European-Non Finnish (NFE) AF: 0.268 AC: 18211 AN: 67972

Other (OTH) AF: 0.298 AC: 630 AN: 2116

Alfa AF: 0.276 Hom.: 4533

Bravo AF: 0.261

TwinsUK AF: 0.273 AC: 1011

ALSPAC AF: 0.274 AC: 1055

ExAC AF: 0.275 AC: 5754

Asia WGS AF: 0.359 AC: 1248 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Van der Woude syndrome 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	5.4
DANN	Benign	0.87
DEOGEN2	Benign	0.27	T
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.048	N
LIST_S2	Benign	0.35	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		-0.29
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.026
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.096
MPC		0.60
ClinPred		0.023	T
GERP RS		-1.2
Varity_R		0.64
gMVP		0.46
Mutation Taster		=99/1	polymorphism (auto)

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: rs545809; hg19: chr1-24690764; COSMIC: COSV50218213; COSMIC: COSV50218213;