rs201106410

Positions:

• chr19-18884227-G-A

Variant summary

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

The NM_001492.6(GDF1):​c.-873C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00182 in 1,613,398 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0019 (4 hom.)
• Consequence: GDF1 NM_001492.6 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.97

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=-0.77).
• BP6: Variant 19-18884227-G-A is Benign according to our data. Variant chr19-18884227-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 475372.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GDF1	NM_001492.6	c.-873C>T		5_prime_UTR_premature_start_codon_gain_variant	3/8	ENST00000247005.8	NP_001483.3
CERS1	NM_021267.5	c.450C>T	p.Ala150Ala	synonymous_variant	3/8	ENST00000623882.4	NP_067090.1
GDF1	NM_001492.6	c.-873C>T		5_prime_UTR_variant	3/8	ENST00000247005.8	NP_001483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GDF1	ENST00000247005.8	c.-873C>T		5_prime_UTR_premature_start_codon_gain_variant	3/8	1	NM_001492.6	ENSP00000247005.5
CERS1	ENST00000623882.4	c.450C>T	p.Ala150Ala	synonymous_variant	3/8	1	NM_021267.5	ENSP00000485308.1
GDF1	ENST00000247005.8	c.-873C>T		5_prime_UTR_variant	3/8	1	NM_001492.6	ENSP00000247005.5

Frequencies

GnomAD3 genomes AF: 0.00130 AC: 198 AN: 151998 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000363

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00269

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000830

Gnomad FIN AF: 0.000472

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00188

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00117 AC: 287 AN: 245376 Hom.: 0 AF XY: 0.00112 AC XY: 150 AN XY: 133566

Gnomad AFR exome AF: 0.000389

Gnomad AMR exome AF: 0.00232

Gnomad ASJ exome AF: 0.0000998

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000622

Gnomad FIN exome AF: 0.000426

Gnomad NFE exome AF: 0.00149

Gnomad OTH exome AF: 0.00133

GnomAD4 exome AF: 0.00188 AC: 2740 AN: 1461282 Hom.: 4 Cov.: 31 AF XY: 0.00180 AC XY: 1308 AN XY: 726920

Gnomad4 AFR exome AF: 0.000448

Gnomad4 AMR exome AF: 0.00248

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000510

Gnomad4 FIN exome AF: 0.000339

Gnomad4 NFE exome AF: 0.00222

Gnomad4 OTH exome AF: 0.00133

GnomAD4 genome AF: 0.00131 AC: 199 AN: 152116 Hom.: 0 Cov.: 31 AF XY: 0.00128 AC XY: 95 AN XY: 74378

Gnomad4 AFR AF: 0.000386

Gnomad4 AMR AF: 0.00269

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000831

Gnomad4 FIN AF: 0.000472

Gnomad4 NFE AF: 0.00188

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00110 Hom.: 0

Bravo AF: 0.00150

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00191

EpiControl AF: 0.00148

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2022

CERS1: BP4, BP7 -

Progressive myoclonic epilepsy type 8 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 05, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.95
DANN	Benign	0.91

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: rs201106410; hg19: chr19-18995036; COSMIC: COSV55928325; COSMIC: COSV55928325;