19-18896036-G-T

Variant names:

• chr19-18896036-G-T
• rs868136098
• NM_021267.5:c.37C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.981
• Publications: 0 publications found

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]

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)

ACMG classification

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	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: 1 AN: 146108 Hom.: 0 Cov.: 30

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: 0 AN: 843714 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 391058

African (AFR) AF: 0.00 AC: 0 AN: 15910

American (AMR) AF: 0.00 AC: 0 AN: 1382

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5342

East Asian (EAS) AF: 0.00 AC: 0 AN: 3992

South Asian (SAS) AF: 0.00 AC: 0 AN: 17344

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1650

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 768786

Other (OTH) AF: 0.00 AC: 0 AN: 27906

GnomAD4 genome AF: 0.00000684 AC: 1 AN: 146108 Hom.: 0 Cov.: 30 AF XY: 0.0000141 AC XY: 1 AN XY: 71040

African (AFR) AF: 0.00 AC: 0 AN: 40758

American (AMR) AF: 0.00 AC: 0 AN: 14730

Ashkenazi Jewish (ASJ) AF: 0.000295 AC: 1 AN: 3386

East Asian (EAS) AF: 0.00 AC: 0 AN: 5048

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8378

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 310

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 65760

Other (OTH) AF: 0.00 AC: 0 AN: 2016

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	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	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	18
DANN	Benign	0.96
DEOGEN2	Benign	0.34	T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.57	T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L
PhyloP100		0.98
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.69	N
REVEL	Benign	0.097
Sift	Benign	0.28	T
Sift4G	Benign	0.32	T
Polyphen		0.52	P
Vest4		0.19
MutPred		0.14		Gain of phosphorylation at P13 (P = 0.0524)
MVP		0.15
ClinPred		0.12	T
GERP RS		3.0
PromoterAI		-0.044	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Varity_R		0.087
Mutation Taster		=93/7	polymorphism

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

Other links and lift over

dbSNP: rs868136098; hg19: chr19-19006845;