Genetic Variant NM_001199013.2:c.738-3145C>T (chr1-24364186-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001199013.2(STPG1):c.738-3145C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0405 in 1,489,000 control chromosomes in the GnomAD database, including 1,419 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.030 ( 98 hom., cov: 33)

Exomes 𝑓: 0.042 ( 1321 hom. )

Consequence

STPG1
NM_001199013.2 intron

Scores

Splicing: ADA: 0.004821

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.0520

Publications

6 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0029179454).

BP6

Variant 1-24364186-G-A is Benign according to our data. Variant chr1-24364186-G-A is described in ClinVar as Benign. ClinVar VariationId is 218865.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0303 (4619/152264) while in subpopulation NFE AF = 0.0472 (3214/68030). AF 95% confidence interval is 0.0459. There are 98 homozygotes in GnomAd4. There are 2185 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 98 AR gene

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
STPG1	NM_001199013.2	MANE Select	c.738-3145C>T		intron	N/A	NP_001185942.1	Q5TH74-1
GRHL3	NM_198174.3		c.1696G>A	p.Glu566Lys	missense splice_region	Exon 16 of 16	NP_937817.3
STPG1	NM_001199012.2		c.738-3145C>T		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.738-3145C>T		intron	N/A	ENSP00000337461.4	Q5TH74-1
STPG1	ENST00000468303.5	TSL:1	n.4211-3145C>T		intron	N/A
GRHL3	ENST00000350501.9	TSL:2	c.1696G>A	p.Glu566Lys	missense splice_region	Exon 16 of 16	ENSP00000288955.5	Q8TE85-1

Frequencies

GnomAD3 genomes

AF:

0.0304

AC:

4625

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00727

Gnomad AMI

AF:

0.0318

Gnomad AMR

AF:

0.0252

Gnomad ASJ

AF:

0.0435

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00932

Gnomad FIN

AF:

0.0395

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.0473

Gnomad OTH

AF:

0.0335

GnomAD2 exomes

AF:

0.0322

AC:

3301

AN:

102552

AF XY:

0.0319

show subpopulations

Gnomad AFR exome

AF:

0.00550

Gnomad AMR exome

AF:

0.0236

Gnomad ASJ exome

AF:

0.0443

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0383

Gnomad NFE exome

AF:

0.0470

Gnomad OTH exome

AF:

0.0422

GnomAD4 exome

AF:

0.0417

AC:

55679

AN:

1336736

Hom.:

1321

Cov.:

AF XY:

0.0409

AC XY:

26767

AN XY:

654368

show subpopulations

African (AFR)

AF:

0.00732

AC:

211

AN:

28840

American (AMR)

AF:

0.0206

AC:

495

AN:

24070

Ashkenazi Jewish (ASJ)

AF:

0.0452

AC:

1020

AN:

22572

East Asian (EAS)

AF:

0.0000300

AC:

AN:

33368

South Asian (SAS)

AF:

0.0102

AC:

715

AN:

70078

European-Finnish (FIN)

AF:

0.0390

AC:

1843

AN:

47230

Middle Eastern (MID)

AF:

0.0284

AC:

155

AN:

5450

European-Non Finnish (NFE)

AF:

0.0469

AC:

49250

AN:

1049788

Other (OTH)

AF:

0.0359

AC:

1989

AN:

55340

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

3040

6079

9119

12158

15198

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1896

3792

5688

7584

9480

<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

AF:

0.0303

AC:

4619

AN:

152264

Hom.:

Cov.:

AF XY:

0.0293

AC XY:

2185

AN XY:

74452

show subpopulations

African (AFR)

AF:

0.00725

AC:

301

AN:

41534

American (AMR)

AF:

0.0251

AC:

384

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0435

AC:

151

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5186

South Asian (SAS)

AF:

0.00932

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0395

AC:

419

AN:

10602

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0472

AC:

3214

AN:

68030

Other (OTH)

AF:

0.0327

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

227

455

682

910

1137

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

162

216

270

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0415

Hom.:

488

Bravo

AF:

0.0294

TwinsUK

AF:

0.0456

AC:

169

ALSPAC

AF:

0.0405

AC:

156

ExAC

AF:

0.0218

AC:

480

Asia WGS

AF:

0.00520

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

GRHL3-related disorder (1)

not provided (1)

not specified (1)

Van der Woude syndrome 2 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.56

CADD

Benign

4.6

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.13

Eigen

Benign

-0.35

Eigen_PC

Benign

-0.53

FATHMM_MKL

Benign

0.042

LIST_S2

Benign

0.42

MetaRNN

Benign

0.0029

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.0

PhyloP100

-0.052

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.020

REVEL

Benign

0.080

Sift

Uncertain

0.010

Sift4G

Uncertain

0.0050

Vest4

0.052

MPC

0.62

ClinPred

0.0044

GERP RS

1.9

Varity_R

0.038

gMVP

0.65

Mutation Taster

=98/2

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0048

dbscSNV1_RF

Benign

0.032

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

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over