rs3746263

Variant names:

• chr19-18895857-G-C
• rs3746263
• NM_021267.5:c.216C>G

Your query was ambiguous. Multiple possible variants found:

• chr19-18895857-G-C
• chr19-18895857-G-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_021267.5(CERS1):​c.216C>G​(p.Ala72Ala) 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:3
• Conservation: PhyloP100: -0.316
• Publications: 11 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: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
CERS1	NM_021267.5	c.216C>G	p.Ala72Ala	synonymous_variant	Exon 1 of 8	ENST00000623882.4	NP_067090.1
GDF1	NM_001492.6	c.-1107C>G		5_prime_UTR_variant	Exon 1 of 8	ENST00000247005.8	NP_001483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CERS1	ENST00000623882.4	c.216C>G	p.Ala72Ala	synonymous_variant	Exon 1 of 8	1	NM_021267.5	ENSP00000485308.1
CERS1	ENST00000429504.6	c.216C>G	p.Ala72Ala	synonymous_variant	Exon 1 of 6	1		ENSP00000389044.1
GDF1	ENST00000247005.8	c.-1107C>G		5_prime_UTR_variant	Exon 1 of 8	1	NM_001492.6	ENSP00000247005.5
CERS1	ENST00000542296.6	c.-46+704C>G		intron_variant	Intron 1 of 5	1		ENSP00000437648.1

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

GnomAD2 exomes AF: 0.570 AC: 9170 AN: 16100 AF XY: 0.564

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 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

African (AFR) AF: 0.801 AC: 17251 AN: 21534

American (AMR) AF: 0.742 AC: 7028 AN: 9468

Ashkenazi Jewish (ASJ) AF: 0.759 AC: 11275 AN: 14860

East Asian (EAS) AF: 0.374 AC: 9031 AN: 24176

South Asian (SAS) AF: 0.507 AC: 23378 AN: 46068

European-Finnish (FIN) AF: 0.550 AC: 14058 AN: 25546

Middle Eastern (MID) AF: 0.810 AC: 2427 AN: 2996

European-Non Finnish (NFE) AF: 0.688 AC: 655393 AN: 952946

Other (OTH) AF: 0.670 AC: 30037 AN: 44852

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

African (AFR) AF: 0.803 AC: 33235 AN: 41376

American (AMR) AF: 0.764 AC: 11636 AN: 15224

Ashkenazi Jewish (ASJ) AF: 0.777 AC: 2688 AN: 3460

East Asian (EAS) AF: 0.372 AC: 1885 AN: 5074

South Asian (SAS) AF: 0.538 AC: 2595 AN: 4820

European-Finnish (FIN) AF: 0.543 AC: 5578 AN: 10266

Middle Eastern (MID) AF: 0.829 AC: 242 AN: 292

European-Non Finnish (NFE) AF: 0.690 AC: 46631 AN: 67630

Other (OTH) AF: 0.730 AC: 1531 AN: 2098

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:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Progressive myoclonic epilepsy type 8 Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	8.2
DANN	Benign	0.77
PhyloP100		-0.32
PromoterAI		-0.083	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Mutation Taster		=300/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3746263; hg19: chr19-19006666; COSMIC: COSV53230339; COSMIC: COSV53230339;