rs760185006

Positions:

• chr19-18895895-G-A
• chr19-18895895-G-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Moderate BP6_Moderate BP7 BS2

The ENST00000623882.4(CERS1):​c.178C>T​(p.Leu60=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000456 in 1,264,130 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. L60L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00048 (2 hom.)
• Consequence: CERS1 ENST00000623882.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.855

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP6: Variant 19-18895895-G-A is Benign according to our data. Variant chr19-18895895-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 542135.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.855 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CERS1	NM_021267.5	c.178C>T	p.Leu60=	synonymous_variant	1/8	ENST00000623882.4	NP_067090.1
GDF1	NM_001492.6	c.-1145C>T		5_prime_UTR_variant	1/8	ENST00000247005.8	NP_001483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CERS1	ENST00000623882.4	c.178C>T	p.Leu60=	synonymous_variant	1/8	1	NM_021267.5	ENSP00000485308	P2
CERS1	ENST00000429504.6	c.178C>T	p.Leu60=	synonymous_variant	1/6	1		ENSP00000389044	A2
GDF1	ENST00000247005.8	c.-1145C>T		5_prime_UTR_variant	1/8	1	NM_001492.6	ENSP00000247005	P1
CERS1	ENST00000542296.6	c.-46+666C>T		intron_variant		1		ENSP00000437648

Frequencies

GnomAD3 genomes AF: 0.000239 AC: 36 AN: 150546 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000970

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000132

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: 0.000430

Gnomad OTH AF: 0.000484

GnomAD3 exomes AF: 0.000638 AC: 7 AN: 10968 Hom.: 0 AF XY: 0.000576 AC XY: 4 AN XY: 6944

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000373

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00144

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000485 AC: 540 AN: 1113584 Hom.: 2 Cov.: 32 AF XY: 0.000518 AC XY: 280 AN XY: 540762

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000116

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000149

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000555

Gnomad4 OTH exome AF: 0.000301

GnomAD4 genome AF: 0.000239 AC: 36 AN: 150546 Hom.: 0 Cov.: 30 AF XY: 0.000218 AC XY: 16 AN XY: 73504

Gnomad4 AFR AF: 0.0000970

Gnomad4 AMR AF: 0.000132

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000430

Gnomad4 OTH AF: 0.000484

Alfa AF: 0.0000540 Hom.: 0

Bravo AF: 0.000204

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Progressive myoclonic epilepsy type 8 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 18, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
CADD	Benign	16
DANN	Uncertain	0.98
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6

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: rs760185006; hg19: chr19-19006704;