chr19-18879243-G-A

Position:

• chr19-18879243-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Moderate BP6_Very_Strong BS2

The NM_001492.6(GDF1):​c.-425C>T variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.000484 in 1,613,654 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00037 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00050 (2 hom.)
• Consequence: GDF1 NM_001492.6 5_prime_UTR_premature_start_codon_gain
• Scores: Splicing: ADA: 0.1064
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 3.67

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 19-18879243-G-A is Benign according to our data. Variant chr19-18879243-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 475378.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-18879243-G-A is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GDF1	NM_001492.6	c.-425C>T		5_prime_UTR_premature_start_codon_gain_variant	5/8	ENST00000247005.8	NP_001483.3
GDF1	NM_001492.6	c.-425C>T		splice_region_variant	5/8	ENST00000247005.8	NP_001483.3
CERS1	NM_021267.5	c.898C>T	p.Leu300Leu	splice_region_variant, synonymous_variant	5/8	ENST00000623882.4	NP_067090.1
GDF1	NM_001492.6	c.-425C>T		5_prime_UTR_variant	5/8	ENST00000247005.8	NP_001483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GDF1	ENST00000247005.8	c.-425C>T		5_prime_UTR_premature_start_codon_gain_variant	5/8	1	NM_001492.6	ENSP00000247005.5
GDF1	ENST00000247005.8	c.-425C>T		splice_region_variant	5/8	1	NM_001492.6	ENSP00000247005.5
CERS1	ENST00000623882.4	c.898C>T	p.Leu300Leu	splice_region_variant, synonymous_variant	5/8	1	NM_021267.5	ENSP00000485308.1
GDF1	ENST00000247005.8	c.-425C>T		5_prime_UTR_variant	5/8	1	NM_001492.6	ENSP00000247005.5

Frequencies

GnomAD3 genomes AF: 0.000368 AC: 56 AN: 152136 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000485

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.000574 AC: 141 AN: 245558 Hom.: 0 AF XY: 0.000622 AC XY: 83 AN XY: 133510

Gnomad AFR exome AF: 0.000130

Gnomad AMR exome AF: 0.000552

Gnomad ASJ exome AF: 0.00130

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.000236

Gnomad NFE exome AF: 0.000781

Gnomad OTH exome AF: 0.00150

GnomAD4 exome AF: 0.000496 AC: 725 AN: 1461400 Hom.: 2 Cov.: 33 AF XY: 0.000527 AC XY: 383 AN XY: 726968

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000559

Gnomad4 ASJ exome AF: 0.00130

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000336

Gnomad4 FIN exome AF: 0.000188

Gnomad4 NFE exome AF: 0.000506

Gnomad4 OTH exome AF: 0.000630

GnomAD4 genome AF: 0.000368 AC: 56 AN: 152254 Hom.: 0 Cov.: 31 AF XY: 0.000376 AC XY: 28 AN XY: 74444

Gnomad4 AFR AF: 0.0000963

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00230

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000830

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000485

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.000588 Hom.: 0

Bravo AF: 0.000355

EpiCase AF: 0.000872

EpiControl AF: 0.000771

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Progressive myoclonic epilepsy type 8 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 12, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	17
DANN	Benign	0.85

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.11
dbscSNV1_RF	Benign	0.23
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: rs373928623; hg19: chr19-18990052;