19-18895839-A-G

Variant names:

• chr19-18895839-A-G
• rs113536478
• NM_021267.5:c.234T>C

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.234T>C​(p.Thr78Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.197 in 1,279,768 control chromosomes in the GnomAD database, including 27,646 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T78T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.25 (5933 hom., cov: 31)
  • Exomes 𝑓: 0.19 (21713 hom.)
• Consequence: CERS1 NM_021267.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.282
• Publications: 4 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=-0.79).
• BP6: Variant 19-18895839-A-G is Benign according to our data. Variant chr19-18895839-A-G is described in ClinVar as Benign. ClinVar VariationId is 137458.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.282 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.443 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CERS1	NM_021267.5	c.234T>C	p.Thr78Thr	synonymous_variant	Exon 1 of 8	ENST00000623882.4	NP_067090.1
GDF1	NM_001492.6	c.-1089T>C		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.234T>C	p.Thr78Thr	synonymous_variant	Exon 1 of 8	1	NM_021267.5	ENSP00000485308.1
CERS1	ENST00000429504.6	c.234T>C	p.Thr78Thr	synonymous_variant	Exon 1 of 6	1		ENSP00000389044.1
GDF1	ENST00000247005.8	c.-1089T>C		5_prime_UTR_variant	Exon 1 of 8	1	NM_001492.6	ENSP00000247005.5
CERS1	ENST00000542296.6	c.-46+722T>C		intron_variant	Intron 1 of 5	1		ENSP00000437648.1

Frequencies

GnomAD3 genomes AF: 0.249 AC: 37629 AN: 151126 Hom.: 5931 Cov.: 31

Gnomad AFR AF: 0.449

Gnomad AMI AF: 0.0793

Gnomad AMR AF: 0.183

Gnomad ASJ AF: 0.196

Gnomad EAS AF: 0.0724

Gnomad SAS AF: 0.189

Gnomad FIN AF: 0.101

Gnomad MID AF: 0.156

Gnomad NFE AF: 0.189

Gnomad OTH AF: 0.219

GnomAD2 exomes AF: 0.0966 AC: 1514 AN: 15678 AF XY: 0.103

Gnomad AFR exome AF: 0.281

Gnomad AMR exome AF: 0.0522

Gnomad ASJ exome AF: 0.105

Gnomad EAS exome AF: 0.0248

Gnomad FIN exome AF: 0.0626

Gnomad NFE exome AF: 0.115

Gnomad OTH exome AF: 0.0647

GnomAD4 exome AF: 0.190 AC: 213914 AN: 1128532 Hom.: 21713 Cov.: 28 AF XY: 0.187 AC XY: 102406 AN XY: 547874

African (AFR) AF: 0.457 AC: 9711 AN: 21254

American (AMR) AF: 0.138 AC: 1224 AN: 8856

Ashkenazi Jewish (ASJ) AF: 0.171 AC: 2473 AN: 14436

East Asian (EAS) AF: 0.0752 AC: 1760 AN: 23410

South Asian (SAS) AF: 0.151 AC: 6725 AN: 44540

European-Finnish (FIN) AF: 0.104 AC: 2583 AN: 24900

Middle Eastern (MID) AF: 0.156 AC: 452 AN: 2898

European-Non Finnish (NFE) AF: 0.191 AC: 180605 AN: 944200

Other (OTH) AF: 0.190 AC: 8381 AN: 44038

GnomAD4 genome AF: 0.249 AC: 37642 AN: 151236 Hom.: 5933 Cov.: 31 AF XY: 0.240 AC XY: 17709 AN XY: 73898

African (AFR) AF: 0.448 AC: 18504 AN: 41308

American (AMR) AF: 0.183 AC: 2787 AN: 15232

Ashkenazi Jewish (ASJ) AF: 0.196 AC: 680 AN: 3462

East Asian (EAS) AF: 0.0724 AC: 366 AN: 5052

South Asian (SAS) AF: 0.188 AC: 901 AN: 4798

European-Finnish (FIN) AF: 0.101 AC: 1052 AN: 10422

Middle Eastern (MID) AF: 0.154 AC: 45 AN: 292

European-Non Finnish (NFE) AF: 0.189 AC: 12779 AN: 67652

Other (OTH) AF: 0.216 AC: 456 AN: 2110

Alfa AF: 0.229 Hom.: 581

Bravo AF: 0.262

Asia WGS AF: 0.138 AC: 478 AN: 3458

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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 -

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	-0.79
CADD	Benign	13
DANN	Benign	0.66
PhyloP100		0.28
PromoterAI		0.049	Neutral
Mutation Taster		=100/0	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: rs113536478; hg19: chr19-19006648; COSMIC: COSV53232444; COSMIC: COSV53232444;