rs45601540

Positions:

• chr19-18884185-G-A
• chr19-18884185-G-C

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_021267.5(CERS1):​c.492C>T​(p.Tyr164=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00905 in 1,613,654 control chromosomes in the GnomAD database, including 100 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0068 (10 hom., cov: 31)
  • Exomes 𝑓: 0.0093 (90 hom.)
• Consequence: CERS1 NM_021267.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.48

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]

ACMG classification

Verdict is Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 19-18884185-G-A is Benign according to our data. Variant chr19-18884185-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 475373.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.48 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CERS1	NM_021267.5	c.492C>T	p.Tyr164=	synonymous_variant	3/8	ENST00000623882.4	NP_067090.1
GDF1	NM_001492.6	c.-831C>T		5_prime_UTR_variant	3/8	ENST00000247005.8	NP_001483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CERS1	ENST00000623882.4	c.492C>T	p.Tyr164=	synonymous_variant	3/8	1	NM_021267.5	ENSP00000485308	P2
GDF1	ENST00000247005.8	c.-831C>T		5_prime_UTR_variant	3/8	1	NM_001492.6	ENSP00000247005	P1

Frequencies

GnomAD3 genomes AF: 0.00678 AC: 1031 AN: 152020 Hom.: 10 Cov.: 31

Gnomad AFR AF: 0.00181

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.0217

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0101

Gnomad OTH AF: 0.00672

GnomAD3 exomes AF: 0.00680 AC: 1674 AN: 246002 Hom.: 17 AF XY: 0.00685 AC XY: 917 AN XY: 133800

Gnomad AFR exome AF: 0.00149

Gnomad AMR exome AF: 0.00136

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000262

Gnomad FIN exome AF: 0.0228

Gnomad NFE exome AF: 0.00977

Gnomad OTH exome AF: 0.00548

GnomAD4 exome AF: 0.00929 AC: 13571 AN: 1461516 Hom.: 90 Cov.: 31 AF XY: 0.00905 AC XY: 6582 AN XY: 727026

Gnomad4 AFR exome AF: 0.00185

Gnomad4 AMR exome AF: 0.00148

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000429

Gnomad4 FIN exome AF: 0.0232

Gnomad4 NFE exome AF: 0.0106

Gnomad4 OTH exome AF: 0.00699

GnomAD4 genome AF: 0.00678 AC: 1031 AN: 152138 Hom.: 10 Cov.: 31 AF XY: 0.00687 AC XY: 511 AN XY: 74382

Gnomad4 AFR AF: 0.00181

Gnomad4 AMR AF: 0.00144

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.0217

Gnomad4 NFE AF: 0.0101

Gnomad4 OTH AF: 0.00665

Alfa AF: 0.00875 Hom.: 8

Bravo AF: 0.00532

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00812

EpiControl AF: 0.00759

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	CERS1: BP4, BP7, BS2 -

Progressive myoclonic epilepsy type 8 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 27, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	0.036
DANN	Benign	0.87

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

LitVar

Other links and lift over

dbSNP: rs45601540; hg19: chr19-18994994;