CERS1 p.Leu340Val

Variant names:

• chr19-18870612-G-C
• rs774114834
• NM_021267.5:c.1018C>G
• CERS1 p.Leu340Val

Your query was ambiguous. Multiple possible variants found:

• chr19-18870612-G-C
• chr19-18870610-CAG-AAC
• chr19-18870610-CAG-GAC
• chr19-18870610-CAG-TAC

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_021267.5(CERS1):​c.1018C>G​(p.Leu340Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000709 in 578,038 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000077 (0 hom.)
• Consequence: CERS1 NM_021267.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.571
• 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: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
• 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007859647).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CERS1	NM_021267.5	MANE Select	c.1018C>G	p.Leu340Val	missense	Exon 7 of 8	NP_067090.1	P27544-1
	GDF1	NM_001492.6	MANE Select	c.-305C>G		5_prime_UTR	Exon 7 of 8	NP_001483.3
	CERS1	NM_001387440.1		c.1018C>G	p.Leu340Val	missense	Exon 7 of 7	NP_001374369.1	P27544-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CERS1	ENST00000623882.4	TSL:1 MANE Select	c.1018C>G	p.Leu340Val	missense	Exon 7 of 8	ENSP00000485308.1	P27544-1
	GDF1	ENST00000247005.8	TSL:1 MANE Select	c.-305C>G		5_prime_UTR	Exon 7 of 8	ENSP00000247005.5	P27539

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152042 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.0000736

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000100 AC: 8 AN: 79898 AF XY: 0.0000704

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000486

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000482

Gnomad OTH exome AF: 0.00137

GnomAD4 exome AF: 0.0000775 AC: 33 AN: 425996 Hom.: 0 Cov.: 0 AF XY: 0.0000892 AC XY: 20 AN XY: 224148

African (AFR) AF: 0.00 AC: 0 AN: 9412

American (AMR) AF: 0.000578 AC: 10 AN: 17312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11974

East Asian (EAS) AF: 0.00 AC: 0 AN: 27616

South Asian (SAS) AF: 0.00 AC: 0 AN: 35924

European-Finnish (FIN) AF: 0.0000222 AC: 1 AN: 45122

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3202

European-Non Finnish (NFE) AF: 0.0000836 AC: 21 AN: 251314

Other (OTH) AF: 0.0000415 AC: 1 AN: 24120

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152042 Hom.: 0 Cov.: 31 AF XY: 0.0000404 AC XY: 3 AN XY: 74246

African (AFR) AF: 0.0000242 AC: 1 AN: 41376

American (AMR) AF: 0.000131 AC: 2 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000736 AC: 5 AN: 67966

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000642

ClinVar

ClinVar submissions

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	0.083
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	19
DANN	Benign	0.94
DEOGEN2	Benign	0.29	T
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.48	T
M_CAP	Benign	0.050	D
MetaRNN	Benign	0.0079	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.47	N
PhyloP100		0.57
Sift4G	Benign	0.36	T
Varity_R		0.086
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs774114834;

hg19: chr19-18981421;