rs3746263

Positions:

• chr19-18895857-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_021267.5(CERS1):​c.216C>G​(p.Ala72=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.678 in 1,293,584 control chromosomes in the GnomAD database, including 301,065 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.71 (38436 hom., cov: 32)
  • Exomes 𝑓: 0.67 (262629 hom.)
• Consequence: CERS1 NM_021267.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.316

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 19-18895857-G-C is Benign according to our data. Variant chr19-18895857-G-C is described in ClinVar as [Benign]. Clinvar id is 402896.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.316 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.796 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CERS1	NM_021267.5	c.216C>G	p.Ala72=	synonymous_variant	1/8	ENST00000623882.4
GDF1	NM_001492.6	c.-1107C>G		5_prime_UTR_variant	1/8	ENST00000247005.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CERS1	ENST00000623882.4	c.216C>G	p.Ala72=	synonymous_variant	1/8	1	NM_021267.5	P2
CERS1	ENST00000429504.6	c.216C>G	p.Ala72=	synonymous_variant	1/6	1		A2
GDF1	ENST00000247005.8	c.-1107C>G		5_prime_UTR_variant	1/8	1	NM_001492.6	P1
CERS1	ENST00000542296.6	c.-46+704C>G		intron_variant		1

Frequencies

GnomAD3 genomes AF: 0.705 AC: 106516 AN: 151030 Hom.: 38418 Cov.: 32

Gnomad AFR AF: 0.804

Gnomad AMI AF: 0.606

Gnomad AMR AF: 0.764

Gnomad ASJ AF: 0.777

Gnomad EAS AF: 0.372

Gnomad SAS AF: 0.539

Gnomad FIN AF: 0.543

Gnomad MID AF: 0.838

Gnomad NFE AF: 0.690

Gnomad OTH AF: 0.737

GnomAD3 exomes AF: 0.570 AC: 9170 AN: 16100 Hom.: 2848 AF XY: 0.564 AC XY: 5811 AN XY: 10306

Gnomad AFR exome AF: 0.659

Gnomad AMR exome AF: 0.647

Gnomad ASJ exome AF: 0.715

Gnomad EAS exome AF: 0.243

Gnomad SAS exome AF: 0.434

Gnomad FIN exome AF: 0.480

Gnomad NFE exome AF: 0.631

Gnomad OTH exome AF: 0.683

GnomAD4 exome AF: 0.674 AC: 769878 AN: 1142446 Hom.: 262629 Cov.: 33 AF XY: 0.671 AC XY: 372976 AN XY: 555826

Gnomad4 AFR exome AF: 0.801

Gnomad4 AMR exome AF: 0.742

Gnomad4 ASJ exome AF: 0.759

Gnomad4 EAS exome AF: 0.374

Gnomad4 SAS exome AF: 0.507

Gnomad4 FIN exome AF: 0.550

Gnomad4 NFE exome AF: 0.688

Gnomad4 OTH exome AF: 0.670

GnomAD4 genome AF: 0.705 AC: 106565 AN: 151138 Hom.: 38436 Cov.: 32 AF XY: 0.693 AC XY: 51178 AN XY: 73798

Gnomad4 AFR AF: 0.803

Gnomad4 AMR AF: 0.764

Gnomad4 ASJ AF: 0.777

Gnomad4 EAS AF: 0.372

Gnomad4 SAS AF: 0.538

Gnomad4 FIN AF: 0.543

Gnomad4 NFE AF: 0.690

Gnomad4 OTH AF: 0.730

Alfa AF: 0.691 Hom.: 4584

Bravo AF: 0.728

Asia WGS AF: 0.446 AC: 1531 AN: 3432

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: MAF -

Progressive myoclonic epilepsy type 8 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	8.2
DANN	Benign	0.77
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: rs3746263; hg19: chr19-19006666; COSMIC: COSV53230339; COSMIC: COSV53230339;