rs868136098

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr19-18896036-G-A
• chr19-18896036-G-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_021267.5(CERS1):​c.37C>T​(p.Pro13Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000213 in 989,926 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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. P13T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00085 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00010 (0 hom.)
• Consequence: CERS1 NM_021267.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3 B: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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07175419).

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>T	p.Pro13Ser	missense	Exon 1 of 8	NP_067090.1
	GDF1	NM_001492.6	MANE Select	c.-1286C>T		5_prime_UTR	Exon 1 of 8	NP_001483.3
	CERS1	NM_001387439.1		c.37C>T	p.Pro13Ser	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>T	p.Pro13Ser	missense	Exon 1 of 8	ENSP00000485308.1
	CERS1	ENST00000429504.6	TSL:1	c.37C>T	p.Pro13Ser	missense	Exon 1 of 6	ENSP00000389044.1
	GDF1	ENST00000247005.8	TSL:1 MANE Select	c.-1286C>T		5_prime_UTR	Exon 1 of 8	ENSP00000247005.5

Frequencies

GnomAD3 genomes AF: 0.000842 AC: 123 AN: 146108 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00280

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000272

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: 0.0000456

Gnomad OTH AF: 0.000992

GnomAD2 exomes AF: 0.00 AC: 0 AN: 42 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000103 AC: 87 AN: 843714 Hom.: 0 Cov.: 31 AF XY: 0.0000921 AC XY: 36 AN XY: 391058

African (AFR) AF: 0.00339 AC: 54 AN: 15910

American (AMR) AF: 0.000724 AC: 1 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: 0.0000351 AC: 27 AN: 768786

Other (OTH) AF: 0.000179 AC: 5 AN: 27906

GnomAD4 genome AF: 0.000848 AC: 124 AN: 146212 Hom.: 0 Cov.: 30 AF XY: 0.000787 AC XY: 56 AN XY: 71154

African (AFR) AF: 0.00281 AC: 115 AN: 40872

American (AMR) AF: 0.000271 AC: 4 AN: 14750

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3386

East Asian (EAS) AF: 0.00 AC: 0 AN: 5032

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.0000456 AC: 3 AN: 65750

Other (OTH) AF: 0.000981 AC: 2 AN: 2038

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Progressive myoclonic epilepsy type 8 (2)
-	-	1	CERS1-related disorder (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.34	T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.58	T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.072	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L
PhyloP100		0.98
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.68	N
REVEL	Benign	0.046
Sift	Benign	0.33	T
Sift4G	Benign	0.41	T
Polyphen		0.52	P
Vest4		0.23
MutPred		0.12		Gain of phosphorylation at P13 (P = 0.0267)
MVP		0.13
ClinPred		0.13	T
GERP RS		3.0
PromoterAI		-0.13	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Varity_R		0.066
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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;