rs760908706

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM1BP4

The NM_001492.6(GDF1):c.985C>T(p.Pro329Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000815 in 1,534,320 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. P329P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000040 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000086 ( 0 hom. )

Consequence

GDF1
NM_001492.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 5.22

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 Uncertain_significance. Variant got 1 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 NM_001492.6

BP4

Computational evidence support a benign effect (MetaRNN=0.36348724).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
GDF1	NM_001492.6 linkuse as main transcript	c.985C>T	p.Pro329Ser	missense_variant	8/8	ENST00000247005.8
CERS1	NM_021267.5 linkuse as main transcript	c.*1254C>T		3_prime_UTR_variant	8/8	ENST00000623882.4
GDF1	NM_001387438.1 linkuse as main transcript	c.985C>T	p.Pro329Ser	missense_variant	5/5
CERS1	NM_001387440.1 linkuse as main transcript	c.*1846C>T		3_prime_UTR_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GDF1	ENST00000247005.8 linkuse as main transcript	c.985C>T	p.Pro329Ser	missense_variant	8/8	1	NM_001492.6	P1
CERS1	ENST00000623882.4 linkuse as main transcript	c.*1254C>T		3_prime_UTR_variant	8/8	1	NM_021267.5	P2	P27544-1

Frequencies

GnomAD3 genomes

AF:

0.0000397

AC:

AN:

151138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000658

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:

0.0000738

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000779

AC:

AN:

141194

Hom.:

AF XY:

0.0000787

AC XY:

AN XY:

76258

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000165

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000379

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000603

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000860

AC:

119

AN:

1383074

Hom.:

Cov.:

AF XY:

0.0000924

AC XY:

AN XY:

682164

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000171

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000780

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000211

Gnomad4 NFE exome

AF:

0.0000757

Gnomad4 OTH exome

AF:

0.0000703

GnomAD4 genome

AF:

0.0000397

AC:

AN:

151246

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

73956

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000657

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000738

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000756

ExAC

AF:

0.0000371

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 15, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Aug 13, 2021	This sequence change replaces proline with serine at codon 329 of the GDF1 protein (p.Pro329Ser). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and serine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This missense change has been observed in individual(s) with clinical features of GDF1-related conditions (Invitae). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 11, 2023

The c.985C>T (p.P329S) alteration is located in exon 8 (coding exon 2) of the GDF1 gene. This alteration results from a C to T substitution at nucleotide position 985, causing the proline (P) at amino acid position 329 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

GDF1-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 24, 2023

The GDF1 c.985C>T variant is predicted to result in the amino acid substitution p.Pro329Ser. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.033% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-18979540-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.23

Cadd

Uncertain

Dann

Uncertain

1.0

DEOGEN2

Pathogenic

0.84

D;.

Eigen

Benign

0.0040

Eigen_PC

Benign

-0.12

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.49

T;.

M_CAP

Pathogenic

0.37

MetaRNN

Benign

0.36

T;T

MetaSVM

Uncertain

0.56

MutationAssessor

Benign

1.7

L;.

MutationTaster

Benign

1.0

D;D

PROVEAN

Pathogenic

-6.8

D;.

REVEL

Uncertain

0.44

Sift

Pathogenic

0.0

D;.

Sift4G

Uncertain

0.023

D;D

Vest4

0.22

MutPred

0.60

Gain of glycosylation at P329 (P = 0.052);Gain of glycosylation at P329 (P = 0.052);

MVP

0.48

MPC

2.1

ClinPred

0.34

GERP RS

3.8

Varity_R

0.78

gMVP

0.84

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