rs4808863

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001492.6(GDF1):c.353C>T(p.Ala118Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.372 in 1,530,440 control chromosomes in the GnomAD database, including 111,915 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A118A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.30 ( 8791 hom., cov: 32)

Exomes 𝑓: 0.38 ( 103124 hom. )

Consequence

GDF1
NM_001492.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 0.0450

Publications

23 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.7131752E-5).

BP6

Variant 19-18869363-G-A is Benign according to our data. Variant chr19-18869363-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 258160.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.461 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
GDF1	NM_001492.6 link	c.353C>T	p.Ala118Val	missense_variant	Exon 8 of 8	ENST00000247005.8	NP_001483.3
CERS1	NM_021267.5 link	c.*622C>T		3_prime_UTR_variant	Exon 8 of 8	ENST00000623882.4	NP_067090.1
GDF1	NM_001387438.1 link	c.353C>T	p.Ala118Val	missense_variant	Exon 5 of 5		NP_001374367.1
CERS1	NM_001387440.1 link	c.*1214C>T		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.353C>T	p.Ala118Val	missense_variant	Exon 8 of 8	1	NM_001492.6	ENSP00000247005.5
CERS1	ENST00000623882.4 link	c.*622C>T		3_prime_UTR_variant	Exon 8 of 8	1	NM_021267.5	ENSP00000485308.1

Frequencies

GnomAD3 genomes

AF:

0.304

AC:

46097

AN:

151626

Hom.:

8785

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0865

Gnomad AMI

AF:

0.308

Gnomad AMR

AF:

0.469

Gnomad ASJ

AF:

0.535

Gnomad EAS

AF:

0.181

Gnomad SAS

AF:

0.241

Gnomad FIN

AF:

0.325

Gnomad MID

AF:

0.442

Gnomad NFE

AF:

0.396

Gnomad OTH

AF:

0.354

GnomAD2 exomes

AF:

0.372

AC:

47398

AN:

127342

AF XY:

0.362

show subpopulations

Gnomad AFR exome

AF:

0.0750

Gnomad AMR exome

AF:

0.527

Gnomad ASJ exome

AF:

0.531

Gnomad EAS exome

AF:

0.186

Gnomad FIN exome

AF:

0.338

Gnomad NFE exome

AF:

0.403

Gnomad OTH exome

AF:

0.421

GnomAD4 exome

AF:

0.379

AC:

522459

AN:

1378704

Hom.:

103124

Cov.:

AF XY:

0.375

AC XY:

255528

AN XY:

680706

show subpopulations

African (AFR)

AF:

0.0724

AC:

2240

AN:

30932

American (AMR)

AF:

0.522

AC:

18620

AN:

35670

Ashkenazi Jewish (ASJ)

AF:

0.534

AC:

13304

AN:

24910

East Asian (EAS)

AF:

0.218

AC:

7664

AN:

35150

South Asian (SAS)

AF:

0.241

AC:

19069

AN:

79070

European-Finnish (FIN)

AF:

0.347

AC:

11605

AN:

33488

Middle Eastern (MID)

AF:

0.453

AC:

1835

AN:

4054

European-Non Finnish (NFE)

AF:

0.396

AC:

427166

AN:

1077886

Other (OTH)

AF:

0.364

AC:

20956

AN:

57544

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

17080

34160

51240

68320

85400

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13318

26636

39954

53272

66590

<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:

0.304

AC:

46105

AN:

151736

Hom.:

8791

Cov.:

AF XY:

0.302

AC XY:

22425

AN XY:

74170

show subpopulations

African (AFR)

AF:

0.0864

AC:

3584

AN:

41486

American (AMR)

AF:

0.470

AC:

7173

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.535

AC:

1849

AN:

3454

East Asian (EAS)

AF:

0.181

AC:

926

AN:

5126

South Asian (SAS)

AF:

0.241

AC:

1159

AN:

4816

European-Finnish (FIN)

AF:

0.325

AC:

3416

AN:

10520

Middle Eastern (MID)

AF:

0.455

AC:

132

AN:

290

European-Non Finnish (NFE)

AF:

0.396

AC:

26850

AN:

67756

Other (OTH)

AF:

0.349

AC:

737

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1454

2909

4363

5818

7272

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

436

872

1308

1744

2180

<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:

0.380

Hom.:

15464

Bravo

AF:

0.310

TwinsUK

AF:

0.401

AC:

1486

ALSPAC

AF:

0.406

AC:

1566

ExAC

AF:

0.247

AC:

20016

Asia WGS

AF:

0.207

AC:

715

AN:

3456

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Jul 29, 2023

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

Significance:Likely 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

- -

Mar 22, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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: 26656983) -

Feb 03, 2025

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

AlphaMissense

Benign

0.090

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.52

CADD

Benign

6.7

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.13

T;.

Eigen

Benign

-0.92

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.090

LIST_S2

Benign

0.43

T;.

MetaRNN

Benign

0.000017

T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

1.1

L;.

PhyloP100

0.045

PROVEAN

Benign

-0.52

N;.

REVEL

Benign

0.11

Sift

Benign

0.52

T;.

Sift4G

Benign

0.34

T;T

Vest4

0.0090

MPC

0.95

ClinPred

0.0025

GERP RS

0.93

Varity_R

0.031

gMVP

0.17

Mutation Taster

=97/3

polymorphism (auto)

(source)

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

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