chr19-18896036-G-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_021267.5(CERS1):c.37C>A(p.Pro13Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 146,108 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P13S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000068 ( 0 hom., cov: 30)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CERS1
NM_021267.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.981

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

right atrial isomerism
Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
congenital heart defects, multiple types, 6
Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: Illumina, Ambry Genetics
conotruncal heart malformations
Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

GDF1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.13441771).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021267.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CERS1	NM_021267.5	MANE Select	c.37C>A	p.Pro13Thr	missense	Exon 1 of 8	NP_067090.1
GDF1	NM_001492.6	MANE Select	c.-1286C>A		5_prime_UTR	Exon 1 of 8	NP_001483.3
CERS1	NM_001387439.1		c.37C>A	p.Pro13Thr	missense	Exon 1 of 7	NP_001374368.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CERS1	ENST00000623882.4	TSL:1 MANE Select	c.37C>A	p.Pro13Thr	missense	Exon 1 of 8	ENSP00000485308.1
CERS1	ENST00000429504.6	TSL:1	c.37C>A	p.Pro13Thr	missense	Exon 1 of 6	ENSP00000389044.1
GDF1	ENST00000247005.8	TSL:1 MANE Select	c.-1286C>A		5_prime_UTR	Exon 1 of 8	ENSP00000247005.5

Frequencies

GnomAD3 genomes

AF:

0.00000684

AC:

AN:

146108

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000295

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

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

843714

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

391058

African (AFR)

AF:

0.00

AC:

AN:

15910

American (AMR)

AF:

0.00

AC:

AN:

1382

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

5342

East Asian (EAS)

AF:

0.00

AC:

AN:

3992

South Asian (SAS)

AF:

0.00

AC:

AN:

17344

European-Finnish (FIN)

AF:

0.00

AC:

AN:

1402

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1650

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

768786

Other (OTH)

AF:

0.00

AC:

AN:

27906

GnomAD4 genome

AF:

0.00000684

AC:

AN:

146108

Hom.:

Cov.:

AF XY:

0.0000141

AC XY:

AN XY:

71040

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

40758

American (AMR)

AF:

0.00

AC:

AN:

14730

Ashkenazi Jewish (ASJ)

AF:

0.000295

AC:

AN:

3386

East Asian (EAS)

AF:

0.00

AC:

AN:

5048

South Asian (SAS)

AF:

0.00

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8378

Middle Eastern (MID)

AF:

0.00

AC:

AN:

310

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

65760

Other (OTH)

AF:

0.00

AC:

AN:

2016

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Progressive myoclonic epilepsy type 8 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.46

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.34

Eigen

Benign

-0.32

Eigen_PC

Benign

-0.33

FATHMM_MKL

Benign

0.65

LIST_S2

Benign

0.57

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.13

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.8

PhyloP100

0.98

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-0.69

REVEL

Benign

0.097

Sift

Benign

0.28

Sift4G

Benign

0.32

Polyphen

0.52

Vest4

0.19

MutPred

0.14

Gain of phosphorylation at P13 (P = 0.0524)

MVP

0.15

ClinPred

0.12

GERP RS

3.0

PromoterAI

-0.044

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.3

Varity_R

0.087

Mutation Taster

=93/7

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over