19-18868791-A-G

Position:

chr19-18868791-A-G

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM1BP4_StrongBP6BS2

The ENST00000247005.8(GDF1):c.925T>C(p.Ser309Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000114 in 1,461,894 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S309S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00011 ( 2 hom. )

Consequence

GDF1
ENST00000247005.8 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

Conservation

PhyloP100: 0.728

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

PM1

In a disulfide_bond (size 70) in uniprot entity GDF1_HUMAN there are 5 pathogenic changes around while only 1 benign (83%) in ENST00000247005.8

BP4

Computational evidence support a benign effect (MetaRNN=0.035881877).

BP6

Variant 19-18868791-A-G is Benign according to our data. Variant chr19-18868791-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 220404.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1, Likely_benign=1}.

BS2

High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
GDF1	NM_001492.6 linkuse as main transcript	c.925T>C	p.Ser309Pro	missense_variant	8/8	ENST00000247005.8	NP_001483.3
CERS1	NM_021267.5 linkuse as main transcript	c.*1194T>C		3_prime_UTR_variant	8/8	ENST00000623882.4	NP_067090.1
GDF1	NM_001387438.1 linkuse as main transcript	c.925T>C	p.Ser309Pro	missense_variant	5/5		NP_001374367.1
CERS1	NM_001387440.1 linkuse as main transcript	c.*1786T>C		3_prime_UTR_variant	7/7		NP_001374369.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GDF1	ENST00000247005.8 linkuse as main transcript	c.925T>C	p.Ser309Pro	missense_variant	8/8	1	NM_001492.6	ENSP00000247005	P1
CERS1	ENST00000623882.4 linkuse as main transcript	c.*1194T>C		3_prime_UTR_variant	8/8	1	NM_021267.5	ENSP00000485308	P2	P27544-1

Frequencies

GnomAD3 genomes

AF:

0.000127

AC:

AN:

149084

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00113

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000975

GnomAD3 exomes

AF:

0.00106

AC:

118

AN:

111764

Hom.:

AF XY:

0.000603

AC XY:

AN XY:

61390

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00566

Gnomad ASJ exome

AF:

0.000137

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000315

GnomAD4 exome

AF:

0.000112

AC:

147

AN:

1312702

Hom.:

Cov.:

AF XY:

0.0000849

AC XY:

AN XY:

647564

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00464

Gnomad4 ASJ exome

AF:

0.0000463

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000764

GnomAD4 genome

AF:

0.000127

AC:

AN:

149192

Hom.:

Cov.:

AF XY:

0.0000686

AC XY:

AN XY:

72852

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00113

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000964

Alfa

AF:

0.000131

Hom.:

Bravo

AF:

0.000298

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

GDF1-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 27, 2023

The GDF1 c.925T>C variant is predicted to result in the amino acid substitution p.Ser309Pro. This variant, which was reported as p.S56P, has previously been identified in one individual with tetralogy of Fallot, aortic root dilation, and pulmonary valve stenosis and functional studies in zebrafish found a reduction in TGFβ signaling compared to controls (Karkera et al. 2007. PubMed ID: 17924340). This variant is reported in 0.57% of alleles in individuals of Latino descent in gnomAD; however, quality metrics at this site indicates the frequency estimate may not be reliable. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Oct 17, 2023

Observed in a patient with tetralogy of Fallot, ventricular septal defect, aortic root dilatation, and bicuspid stenotic pulmonary valve stenosis (Karkera et al., 2007); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 19553149, 17924340) -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Jul 18, 2023

- -

Progressive myoclonic epilepsy type 8

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 15, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.048

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.16

CADD

Benign

6.1

DANN

Benign

0.46

DEOGEN2

Uncertain

0.54

D;.

Eigen

Benign

-0.90

Eigen_PC

Benign

-0.99

FATHMM_MKL

Benign

0.023

LIST_S2

Benign

0.29

T;.

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.036

T;T

MetaSVM

Benign

-0.81

MutationAssessor

Benign

-0.46

N;.

MutationTaster

Benign

0.99

N;N

PROVEAN

Benign

-2.0

N;.

REVEL

Uncertain

0.53

Sift

Benign

0.25

T;.

Sift4G

Benign

0.31

T;T

Vest4

0.65

MutPred

0.80

Loss of catalytic residue at S309 (P = 0.0214);Loss of catalytic residue at S309 (P = 0.0214);

MVP

0.47

MPC

1.2

ClinPred

0.021

GERP RS

0.87

Varity_R

0.18

gMVP

0.68

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over