19-18884127-C-T

Position:

chr19-18884127-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.

The NM_001492.6(GDF1):c.-773G>A variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000109 in 1,613,412 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

GDF1
NM_001492.6 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.53

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 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GDF1	NM_001492.6 linkuse as main transcript	c.-773G>A		5_prime_UTR_premature_start_codon_gain_variant	3/8	ENST00000247005.8	NP_001483.3	P27539A0A024R7N8
CERS1	NM_021267.5 linkuse as main transcript	c.550G>A	p.Val184Met	missense_variant	3/8	ENST00000623882.4	NP_067090.1	P27544-1
GDF1	NM_001492.6 linkuse as main transcript	c.-773G>A		5_prime_UTR_variant	3/8	ENST00000247005.8	NP_001483.3	P27539A0A024R7N8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
GDF1	ENST00000247005.8 linkuse as main transcript	c.-773G>A		5_prime_UTR_premature_start_codon_gain_variant	3/8	1	NM_001492.6	ENSP00000247005.5	P27539
CERS1	ENST00000623882.4 linkuse as main transcript	c.550G>A	p.Val184Met	missense_variant	3/8	1	NM_021267.5	ENSP00000485308.1	P27544-1
GDF1	ENST00000247005.8 linkuse as main transcript	c.-773G>A		5_prime_UTR_variant	3/8	1	NM_001492.6	ENSP00000247005.5	P27539

Frequencies

GnomAD3 genomes

AF:

0.0000395

AC:

AN:

152040

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000416

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000448

AC:

AN:

245722

Hom.:

AF XY:

0.0000599

AC XY:

AN XY:

133650

show subpopulations

Gnomad AFR exome

AF:

0.0000646

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000983

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000545

Gnomad OTH exome

AF:

0.000166

GnomAD4 exome

AF:

0.000116

AC:

170

AN:

1461372

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

726932

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000104

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000135

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.0000395

AC:

AN:

152040

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74238

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000416

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000773

Hom.:

Bravo

AF:

0.0000491

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000577

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Progressive myoclonic epilepsy type 8

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 19, 2022

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 184 of the CERS1 protein (p.Val184Met). This variant is present in population databases (rs374308521, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with CERS1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1017659). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.091

BayesDel_noAF

Benign

-0.16

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.76

D;.;D

Eigen

Uncertain

0.40

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Benign

0.65

LIST_S2

Uncertain

0.93

D;D;D

M_CAP

Uncertain

0.28

MetaRNN

Uncertain

0.46

T;T;T

MetaSVM

Uncertain

0.64

MutationAssessor

Uncertain

2.6

M;M;.

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-1.5

.;N;N

REVEL

Uncertain

0.63

Sift

Uncertain

0.0090

.;D;D

Sift4G

Uncertain

0.022

D;D;D

Polyphen

1.0

D;.;.

Vest4

0.39

MVP

0.73

ClinPred

0.41

GERP RS

4.4

Varity_R

0.19

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