19-18869245-TGCCGCCGCC-TGCCGCCGCCGCC

Variant names:

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP3BP6_Very_StrongBA1

The NM_001492.6(GDF1):c.468_470dupGGC(p.Ala157dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0489 in 1,427,884 control chromosomes in the GnomAD database, including 1,635 homozygotes. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.042 ( 170 hom., cov: 32)

Exomes 𝑓: 0.050 ( 1465 hom. )

Consequence

GDF1
NM_001492.6 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.179

Publications

6 publications found

Variant links:

Genes affected

GDF1 (HGNC:4214): (growth differentiation factor 1) This gene encodes a secreted ligand of the TGF-beta (transforming growth factor-beta) superfamily of proteins. Ligands of this family bind various TGF-beta receptors leading to recruitment and activation of SMAD family transcription factors that regulate gene expression. The encoded preproprotein is proteolytically processed to generate each subunit of the disulfide-linked homodimer. Studies in rodents suggest that this protein is involved in the establishment of left-right asymmetry in early embryogenesis and in neural development in later embryogenesis. The encoded protein is translated from a bicistronic mRNA that also encodes ceramide synthase 1. Mutations in this gene are associated with several congenital cardiovascular malformations. [provided by RefSeq, Jul 2016]

GDF1 links:

CERS1 (HGNC:14253): (ceramide synthase 1) This gene encodes a ceramide synthase enzyme, which catalyzes the synthesis of ceramide, the hydrophobic moiety of sphingolipids. The encoded enzyme synthesizes 18-carbon (C18) ceramide in brain neurons. Elevated expression of this gene may be associated with increased longevity, while decreased expression of this gene may be associated with myoclonus epilepsy with dementia in human patients. This protein is transcribed from a monocistronic mRNA as well as a bicistronic mRNA, which also encodes growth differentiation factor 1. [provided by RefSeq, Jul 2016]

CERS1 Gene-Disease associations (from GenCC):

progressive myoclonic epilepsy type 8
Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)

CERS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -17 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_001492.6

BP6

Variant 19-18869245-T-TGCC is Benign according to our data. Variant chr19-18869245-T-TGCC is described in ClinVar as Benign. ClinVar VariationId is 215496.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0926 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GDF1	NM_001492.6 link	c.468_470dupGGC	p.Ala157dup	disruptive_inframe_insertion	Exon 8 of 8	ENST00000247005.8	NP_001483.3	P27539A0A024R7N8
CERS1	NM_021267.5 link	c.737_739dupGGC		3_prime_UTR_variant	Exon 8 of 8	ENST00000623882.4	NP_067090.1	P27544-1
GDF1	NM_001387438.1 link	c.468_470dupGGC	p.Ala157dup	disruptive_inframe_insertion	Exon 5 of 5		NP_001374367.1
CERS1	NM_001387440.1 link	c.1329_1331dupGGC		3_prime_UTR_variant	Exon 7 of 7		NP_001374369.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GDF1	ENST00000247005.8 link	c.468_470dupGGC	p.Ala157dup	disruptive_inframe_insertion	Exon 8 of 8	1	NM_001492.6	ENSP00000247005.5		P27539
CERS1	ENST00000623882.4 link	c.737_739dupGGC		3_prime_UTR_variant	Exon 8 of 8	1	NM_021267.5	ENSP00000485308.1		P27544-1

Frequencies

GnomAD3 genomes

AF:

0.0425

AC:

6391

AN:

150494

Hom.:

169

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0155

Gnomad AMI

AF:

0.126

Gnomad AMR

AF:

0.0392

Gnomad ASJ

AF:

0.0596

Gnomad EAS

AF:

0.0998

Gnomad SAS

AF:

0.00869

Gnomad FIN

AF:

0.0659

Gnomad MID

AF:

0.0764

Gnomad NFE

AF:

0.0515

Gnomad OTH

AF:

0.0620

GnomAD2 exomes

AF:

0.0383

AC:

1196

AN:

31234

AF XY:

0.0372

show subpopulations

Gnomad AFR exome

AF:

0.0226

Gnomad AMR exome

AF:

0.0251

Gnomad ASJ exome

AF:

0.0566

Gnomad EAS exome

AF:

0.0789

Gnomad FIN exome

AF:

0.0654

Gnomad NFE exome

AF:

0.0505

Gnomad OTH exome

AF:

0.0403

GnomAD4 exome

AF:

0.0496

AC:

63364

AN:

1277286

Hom.:

1465

Cov.:

AF XY:

0.0492

AC XY:

30869

AN XY:

627722

show subpopulations

African (AFR)

AF:

0.0139

AC:

347

AN:

24918

American (AMR)

AF:

0.0266

AC:

512

AN:

19252

Ashkenazi Jewish (ASJ)

AF:

0.0571

AC:

1119

AN:

19586

East Asian (EAS)

AF:

0.0696

AC:

1949

AN:

27996

South Asian (SAS)

AF:

0.00876

AC:

562

AN:

64138

European-Finnish (FIN)

AF:

0.0612

AC:

1886

AN:

30796

Middle Eastern (MID)

AF:

0.0433

AC:

158

AN:

3650

European-Non Finnish (NFE)

AF:

0.0525

AC:

54309

AN:

1034266

Other (OTH)

AF:

0.0479

AC:

2522

AN:

52684

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

2878

5756

8635

11513

14391

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2152

4304

6456

8608

10760

<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:

0.0424

AC:

6390

AN:

150598

Hom.:

170

Cov.:

AF XY:

0.0438

AC XY:

3225

AN XY:

73606

show subpopulations

African (AFR)

AF:

0.0155

AC:

640

AN:

41378

American (AMR)

AF:

0.0392

AC:

595

AN:

15168

Ashkenazi Jewish (ASJ)

AF:

0.0596

AC:

205

AN:

3442

East Asian (EAS)

AF:

0.0997

AC:

512

AN:

5136

South Asian (SAS)

AF:

0.00849

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0659

AC:

657

AN:

9974

Middle Eastern (MID)

AF:

0.0788

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0516

AC:

3474

AN:

67384

Other (OTH)

AF:

0.0614

AC:

128

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

304

608

911

1215

1519

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

148

222

296

370

<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:

0.0166

Hom.:

Bravo

AF:

0.0420

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Apr 17, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 24, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: GDF1 c.468_470dupGGC (p.Ala158dup) results in an in-frame duplication that is predicted to duplicate one amino acid in the encoded protein. The variant allele was found at a frequency of 0.038 in 31234 control chromosomes in the gnomAD database, including 25 homozygotes. The observed variant frequency is approximately 30000-fold of the estimated maximal expected allele frequency for a pathogenic variant in GDF1 causing Congenital Heart Disease phenotype (1.3e-06). c.468_470dupGGC has been reported in the literature in individuals affected with Congenital Heart Disease (e.g. Meng_2017), however these report(s) do not provide unequivocal conclusions about association of the variant with Congenital Heart Disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 215496). Based on the evidence outlined above, the variant was classified as benign. -

Visceral heterotaxy

Benign:1

Mar 11, 2016

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 31180159, 28973083) -

Progressive myoclonic epilepsy type 8

Benign:1

Dec 18, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.18

Mutation Taster

=85/15

polymorphism (auto)

(source)

Splicing

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over