rs146219830

Positions:

• chr19-18869963-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001387440.1(CERS1):​c.*614G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00534 in 1,569,272 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0036 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0055 (29 hom.)
• Consequence: CERS1 NM_001387440.1 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.0770

Genes affected

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]

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 19-18869963-C-T is Benign according to our data. Variant chr19-18869963-C-T is described in ClinVar as [Benign]. Clinvar id is 137457.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GDF1	NM_001492.6	c.325+20G>A		intron_variant		ENST00000247005.8	NP_001483.3
CERS1	NM_021267.5	c.*594+20G>A		intron_variant		ENST00000623882.4	NP_067090.1
CERS1	NM_001387440.1	c.*614G>A		3_prime_UTR_variant	7/7		NP_001374369.1
GDF1	NM_001387438.1	c.325+20G>A		intron_variant			NP_001374367.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GDF1	ENST00000247005.8	c.325+20G>A		intron_variant		1	NM_001492.6	ENSP00000247005.5
CERS1	ENST00000623882.4	c.*594+20G>A		intron_variant		1	NM_021267.5	ENSP00000485308.1

Frequencies

GnomAD3 genomes AF: 0.00359 AC: 547 AN: 152180 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000893

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00301

Gnomad ASJ AF: 0.0228

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00540

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00423 AC: 743 AN: 175562 Hom.: 4 AF XY: 0.00390 AC XY: 374 AN XY: 95830

Gnomad AFR exome AF: 0.000879

Gnomad AMR exome AF: 0.00161

Gnomad ASJ exome AF: 0.0221

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000205

Gnomad FIN exome AF: 0.00156

Gnomad NFE exome AF: 0.00608

Gnomad OTH exome AF: 0.00528

GnomAD4 exome AF: 0.00552 AC: 7826 AN: 1416974 Hom.: 29 Cov.: 33 AF XY: 0.00538 AC XY: 3775 AN XY: 701522

Gnomad4 AFR exome AF: 0.000900

Gnomad4 AMR exome AF: 0.00187

Gnomad4 ASJ exome AF: 0.0245

Gnomad4 EAS exome AF: 0.0000272

Gnomad4 SAS exome AF: 0.000186

Gnomad4 FIN exome AF: 0.00124

Gnomad4 NFE exome AF: 0.00616

Gnomad4 OTH exome AF: 0.00509

GnomAD4 genome AF: 0.00360 AC: 548 AN: 152298 Hom.: 4 Cov.: 32 AF XY: 0.00342 AC XY: 255 AN XY: 74470

Gnomad4 AFR AF: 0.000890

Gnomad4 AMR AF: 0.00300

Gnomad4 ASJ AF: 0.0228

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00113

Gnomad4 NFE AF: 0.00541

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00617 Hom.: 1

Bravo AF: 0.00379

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 06, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 15, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	8.4
DANN	Benign	0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs146219830; hg19: chr19-18980772;