rs578219025

Positions:

• chr19-18869398-G-A
• chr19-18869398-G-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_001492.6(GDF1):​c.326-8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000281 in 1,528,356 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0016 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: GDF1 NM_001492.6 splice_region, intron
• Scores: Splicing: ADA: 0.00003503
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.272

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 19-18869398-G-A is Benign according to our data. Variant chr19-18869398-G-A is described in ClinVar as [Benign]. Clinvar id is 539307.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GDF1	NM_001492.6	c.326-8C>T		splice_region_variant, intron_variant		ENST00000247005.8	NP_001483.3
CERS1	NM_021267.5	c.*595-8C>T		splice_region_variant, intron_variant		ENST00000623882.4	NP_067090.1
CERS1	NM_001387440.1	c.*1179C>T		3_prime_UTR_variant	7/7		NP_001374369.1
GDF1	NM_001387438.1	c.326-8C>T		splice_region_variant, intron_variant			NP_001374367.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GDF1	ENST00000247005.8	c.326-8C>T		splice_region_variant, intron_variant		1	NM_001492.6	ENSP00000247005.5
CERS1	ENST00000623882.4	c.*595-8C>T		splice_region_variant, intron_variant		1	NM_021267.5	ENSP00000485308.1

Frequencies

GnomAD3 genomes AF: 0.00155 AC: 236 AN: 151990 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00539

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000370 AC: 46 AN: 124364 Hom.: 0 AF XY: 0.000366 AC XY: 25 AN XY: 68340

Gnomad AFR exome AF: 0.00652

Gnomad AMR exome AF: 0.000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000450

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000524

GnomAD4 exome AF: 0.000140 AC: 193 AN: 1376258 Hom.: 0 Cov.: 36 AF XY: 0.000128 AC XY: 87 AN XY: 679264

Gnomad4 AFR exome AF: 0.00501

Gnomad4 AMR exome AF: 0.000367

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000127

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000186

Gnomad4 OTH exome AF: 0.000366

GnomAD4 genome AF: 0.00156 AC: 237 AN: 152098 Hom.: 1 Cov.: 32 AF XY: 0.00155 AC XY: 115 AN XY: 74374

Gnomad4 AFR AF: 0.00539

Gnomad4 AMR AF: 0.000784

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000855 Hom.: 0

Bravo AF: 0.00170

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 04, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	4.7
DANN	Benign	0.90

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000035
dbscSNV1_RF	Benign	0.016
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: rs578219025; hg19: chr19-18980207;