rs374282355

Variant names:

• chr19-18870318-G-A
• rs374282355
• NM_001492.6:c.-11C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-18870318-G-A
• chr19-18870318-G-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001492.6(GDF1):​c.-11C>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 0.000461 in 1,545,224 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0023 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00026 (5 hom.)
• Consequence: GDF1 NM_001492.6 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.874

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 19-18870318-G-A is Benign according to our data. Variant chr19-18870318-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 258159.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome4 at 5 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GDF1	NM_001492.6	c.-11C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 7 of 8	ENST00000247005.8	NP_001483.3
GDF1	NM_001492.6	c.-11C>T		5_prime_UTR_variant	Exon 7 of 8	ENST00000247005.8	NP_001483.3
CERS1	NM_021267.5	c.*259C>T		3_prime_UTR_variant	Exon 7 of 8	ENST00000623882.4	NP_067090.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GDF1	ENST00000247005.8	c.-11C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 7 of 8	1	NM_001492.6	ENSP00000247005.5
GDF1	ENST00000247005.8	c.-11C>T		5_prime_UTR_variant	Exon 7 of 8	1	NM_001492.6	ENSP00000247005.5
CERS1	ENST00000623882	c.*259C>T		3_prime_UTR_variant	Exon 7 of 8	1	NM_021267.5	ENSP00000485308.1

Frequencies

GnomAD3 genomes AF: 0.00228 AC: 347 AN: 151912 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00820

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000407 AC: 56 AN: 137424 Hom.: 0 AF XY: 0.000254 AC XY: 19 AN XY: 74704

Gnomad AFR exome AF: 0.00827

Gnomad AMR exome AF: 0.000205

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000261 AC: 364 AN: 1393198 Hom.: 5 Cov.: 34 AF XY: 0.000214 AC XY: 147 AN XY: 687286

Gnomad4 AFR exome AF: 0.00986

Gnomad4 AMR exome AF: 0.000365

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000253

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000556

Gnomad4 OTH exome AF: 0.000571

GnomAD4 genome AF: 0.00229 AC: 348 AN: 152026 Hom.: 0 Cov.: 32 AF XY: 0.00227 AC XY: 169 AN XY: 74332

Gnomad4 AFR AF: 0.00820

Gnomad4 AMR AF: 0.000393

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00199 Hom.: 0

Bravo AF: 0.00274

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	11
DANN	Benign	0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs374282355; hg19: chr19-18981127;