19-18879243-G-A

Variant names:

• chr19-18879243-G-A
• rs373928623
• NM_001492.6:c.-425C>T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 0 publications found

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]

CERS1 Gene-Disease associations (from GenCC):

• progressive myoclonic epilepsy type 8

  Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
• progressive myoclonus epilepsy

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 475378.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 2 AD,AR,Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001492.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GDF1	NM_001492.6	MANE Select	c.-425C>T		5_prime_UTR_premature_start_codon_gain	Exon 5 of 8	NP_001483.3
	GDF1	NM_001492.6	MANE Select	c.-425C>T		splice_region	Exon 5 of 8	NP_001483.3
	CERS1	NM_021267.5	MANE Select	c.898C>T	p.Leu300Leu	splice_region synonymous	Exon 5 of 8	NP_067090.1	P27544-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GDF1	ENST00000247005.8	TSL:1 MANE Select	c.-425C>T		5_prime_UTR_premature_start_codon_gain	Exon 5 of 8	ENSP00000247005.5	P27539
	GDF1	ENST00000247005.8	TSL:1 MANE Select	c.-425C>T		splice_region	Exon 5 of 8	ENSP00000247005.5	P27539
	CERS1	ENST00000623882.4	TSL:1 MANE Select	c.898C>T	p.Leu300Leu	splice_region synonymous	Exon 5 of 8	ENSP00000485308.1	P27544-1

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

GnomAD2 exomes AF: 0.000574 AC: 141 AN: 245558 AF XY: 0.000622

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 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

African (AFR) AF: 0.0000597 AC: 2 AN: 33478

American (AMR) AF: 0.000559 AC: 25 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.00130 AC: 34 AN: 26102

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.000336 AC: 29 AN: 86210

European-Finnish (FIN) AF: 0.000188 AC: 10 AN: 53316

Middle Eastern (MID) AF: 0.00416 AC: 24 AN: 5764

European-Non Finnish (NFE) AF: 0.000506 AC: 563 AN: 1111786

Other (OTH) AF: 0.000630 AC: 38 AN: 60360

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

African (AFR) AF: 0.0000963 AC: 4 AN: 41544

American (AMR) AF: 0.000196 AC: 3 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00230 AC: 8 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

South Asian (SAS) AF: 0.000830 AC: 4 AN: 4820

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000485 AC: 33 AN: 68006

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.000588 Hom.: 0

Bravo AF: 0.000355

EpiCase AF: 0.000872

EpiControl AF: 0.000771

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Progressive myoclonic epilepsy type 8 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	17
DANN	Benign	0.85
PhyloP100		3.7
Mutation Taster		=85/15	polymorphism

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

Other links and lift over

dbSNP: rs373928623; hg19: chr19-18990052;