chr19-18896057-G-T

Position:

chr19-18896057-G-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6

The NM_021267.5(CERS1):c.16C>A(p.Pro6Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000146 in 982,440 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P6R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00064 ( 0 hom., cov: 30)

Exomes 𝑓: 0.000060 ( 0 hom. )

Consequence

CERS1
NM_021267.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: -1.47

Variant links:

Genes affected

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:

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.02537322).

BP6

Variant 19-18896057-G-T is Benign according to our data. Variant chr19-18896057-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 542128.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CERS1	NM_021267.5 linkuse as main transcript	c.16C>A	p.Pro6Thr	missense_variant	1/8	ENST00000623882.4
GDF1	NM_001492.6 linkuse as main transcript	c.-1307C>A		5_prime_UTR_variant	1/8	ENST00000247005.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CERS1	ENST00000623882.4 linkuse as main transcript	c.16C>A	p.Pro6Thr	missense_variant	1/8	1	NM_021267.5	P2	P27544-1
CERS1	ENST00000429504.6 linkuse as main transcript	c.16C>A	p.Pro6Thr	missense_variant	1/6	1		A2	P27544-2
GDF1	ENST00000247005.8 linkuse as main transcript	c.-1307C>A		5_prime_UTR_variant	1/8	1	NM_001492.6	P1
CERS1	ENST00000542296.6 linkuse as main transcript	c.-46+504C>A		intron_variant		1

Frequencies

GnomAD3 genomes

AF:

0.000636

AC:

AN:

146138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00226

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000679

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:

0.00

GnomAD4 exome

AF:

0.0000598

AC:

AN:

836198

Hom.:

Cov.:

AF XY:

0.0000543

AC XY:

AN XY:

386830

show subpopulations

Gnomad4 AFR exome

AF:

0.00304

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

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:

0.0000727

GnomAD4 genome

AF:

0.000636

AC:

AN:

146242

Hom.:

Cov.:

AF XY:

0.000576

AC XY:

AN XY:

71176

show subpopulations

Gnomad4 AFR

AF:

0.00225

Gnomad4 AMR

AF:

0.0000678

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:

0.00

Alfa

AF:

0.000498

Hom.:

Bravo

AF:

0.000740

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 03, 2022

The c.16C>A (p.P6T) alteration is located in exon 1 (coding exon 1) of the CERS1 gene. This alteration results from a C to A substitution at nucleotide position 16, causing the proline (P) at amino acid position 6 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Progressive myoclonic epilepsy type 8

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 05, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.77

CADD

Benign

0.48

DANN

Benign

0.71

DEOGEN2

Benign

0.28

T;.

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.0084

LIST_S2

Benign

0.26

T;T

M_CAP

Benign

0.0064

MetaRNN

Benign

0.025

T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.1

L;L

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Uncertain

0.74

PROVEAN

Benign

-0.25

.;N

REVEL

Benign

0.016

Sift

Benign

1.0

.;T

Sift4G

Benign

0.55

T;T

Polyphen

0.0

B;.

Vest4

0.036

MutPred

0.12

Gain of phosphorylation at P6 (P = 0.04);Gain of phosphorylation at P6 (P = 0.04);

MVP

0.030

ClinPred

0.034

GERP RS

-5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.6

Varity_R

0.026

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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