rs45601540

Variant names:

• chr19-18884185-G-A
• rs45601540
• NM_001492.6:c.-831C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-18884185-G-A
• chr19-18884185-G-C

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001492.6(GDF1):​c.-831C>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 0.00905 in 1,613,654 control chromosomes in the GnomAD database, including 100 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0068 (10 hom., cov: 31)
  • Exomes 𝑓: 0.0093 (90 hom.)
• Consequence: GDF1 NM_001492.6 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.48
• Publications: 3 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 19-18884185-G-A is Benign according to our data. Variant chr19-18884185-G-A is described in ClinVar as Benign. ClinVar VariationId is 475373.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 10 AD,Unknown,AR 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.-831C>T		5_prime_UTR_premature_start_codon_gain	Exon 3 of 8	NP_001483.3
	CERS1	NM_021267.5	MANE Select	c.492C>T	p.Tyr164Tyr	synonymous	Exon 3 of 8	NP_067090.1	P27544-1
	GDF1	NM_001492.6	MANE Select	c.-831C>T		5_prime_UTR	Exon 3 of 8	NP_001483.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GDF1	ENST00000247005.8	TSL:1 MANE Select	c.-831C>T		5_prime_UTR_premature_start_codon_gain	Exon 3 of 8	ENSP00000247005.5	P27539
	CERS1	ENST00000623882.4	TSL:1 MANE Select	c.492C>T	p.Tyr164Tyr	synonymous	Exon 3 of 8	ENSP00000485308.1	P27544-1
	CERS1	ENST00000429504.6	TSL:1	c.492C>T	p.Tyr164Tyr	synonymous	Exon 3 of 6	ENSP00000389044.1	P27544-2

Frequencies

GnomAD3 genomes AF: 0.00678 AC: 1031 AN: 152020 Hom.: 10 Cov.: 31

Gnomad AFR AF: 0.00181

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.0217

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0101

Gnomad OTH AF: 0.00672

GnomAD2 exomes AF: 0.00680 AC: 1674 AN: 246002 AF XY: 0.00685

Gnomad AFR exome AF: 0.00149

Gnomad AMR exome AF: 0.00136

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0228

Gnomad NFE exome AF: 0.00977

Gnomad OTH exome AF: 0.00548

GnomAD4 exome AF: 0.00929 AC: 13571 AN: 1461516 Hom.: 90 Cov.: 31 AF XY: 0.00905 AC XY: 6582 AN XY: 727026

African (AFR) AF: 0.00185 AC: 62 AN: 33480

American (AMR) AF: 0.00148 AC: 66 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.0000765 AC: 2 AN: 26130

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

South Asian (SAS) AF: 0.000429 AC: 37 AN: 86232

European-Finnish (FIN) AF: 0.0232 AC: 1237 AN: 53322

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0106 AC: 11745 AN: 1111812

Other (OTH) AF: 0.00699 AC: 422 AN: 60368

GnomAD4 genome AF: 0.00678 AC: 1031 AN: 152138 Hom.: 10 Cov.: 31 AF XY: 0.00687 AC XY: 511 AN XY: 74382

African (AFR) AF: 0.00181 AC: 75 AN: 41508

American (AMR) AF: 0.00144 AC: 22 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4808

European-Finnish (FIN) AF: 0.0217 AC: 230 AN: 10604

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

European-Non Finnish (NFE) AF: 0.0101 AC: 688 AN: 67992

Other (OTH) AF: 0.00665 AC: 14 AN: 2106

Alfa AF: 0.00814 Hom.: 13

Bravo AF: 0.00532

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00812

EpiControl AF: 0.00759

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Progressive myoclonic epilepsy type 8 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	0.036
DANN	Benign	0.87
PhyloP100		-1.5
PromoterAI		-0.0012	Neutral
Mutation Taster		=292/8	polymorphism

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

Other links and lift over

dbSNP: rs45601540; hg19: chr19-18994994;