rs4808864

Variant names:

• chr19-18869404-A-G
• rs4808864
• NM_001492.6:c.326-14T>C

Your query was ambiguous. Multiple possible variants found:

• chr19-18869404-A-G
• chr19-18869404-A-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001492.6(GDF1):​c.326-14T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 1 in 1,528,212 control chromosomes in the GnomAD database, including 763,778 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 1.0 (75962 hom., cov: 28)
  • Exomes 𝑓: 1.0 (687816 hom.)
• Consequence: GDF1 NM_001492.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.701
• Publications: 8 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: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 19-18869404-A-G is Benign according to our data. Variant chr19-18869404-A-G is described in ClinVar as Benign. ClinVar VariationId is 198776.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.993 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GDF1	NM_001492.6	MANE Select	c.326-14T>C		intron	N/A	NP_001483.3
	CERS1	NM_021267.5	MANE Select	c.*595-14T>C		intron	N/A	NP_067090.1
	CERS1	NM_001387440.1		c.*1173T>C		3_prime_UTR	Exon 7 of 7	NP_001374369.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GDF1	ENST00000247005.8	TSL:1 MANE Select	c.326-14T>C		intron	N/A	ENSP00000247005.5
	CERS1	ENST00000623882.4	TSL:1 MANE Select	c.*595-14T>C		intron	N/A	ENSP00000485308.1

Frequencies

GnomAD3 genomes AF: 1.00 AC: 151831 AN: 151846 Hom.: 75908 Cov.: 28

Gnomad AFR AF: 1.00

Gnomad AMI AF: 1.00

Gnomad AMR AF: 1.00

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 1.00

Gnomad MID AF: 1.00

Gnomad NFE AF: 1.00

Gnomad OTH AF: 1.00

GnomAD2 exomes AF: 1.00 AC: 124120 AN: 124130 AF XY: 1.00

Gnomad AFR exome AF: 1.00

Gnomad AMR exome AF: 1.00

Gnomad ASJ exome AF: 1.00

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 1.00

Gnomad OTH exome AF: 1.00

GnomAD4 exome AF: 1.00 AC: 1375945 AN: 1376258 Hom.: 687816 Cov.: 45 AF XY: 1.00 AC XY: 679103 AN XY: 679268

African (AFR) AF: 1.00 AC: 30855 AN: 30856

American (AMR) AF: 1.00 AC: 35363 AN: 35364

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 24833 AN: 24834

East Asian (EAS) AF: 1.00 AC: 34954 AN: 34954

South Asian (SAS) AF: 1.00 AC: 78964 AN: 78964

European-Finnish (FIN) AF: 1.00 AC: 33358 AN: 33358

Middle Eastern (MID) AF: 1.00 AC: 4042 AN: 4042

European-Non Finnish (NFE) AF: 1.00 AC: 1076137 AN: 1076444

Other (OTH) AF: 1.00 AC: 57439 AN: 57442

GnomAD4 genome AF: 1.00 AC: 151939 AN: 151954 Hom.: 75962 Cov.: 28 AF XY: 1.00 AC XY: 74252 AN XY: 74258

African (AFR) AF: 1.00 AC: 41473 AN: 41474

American (AMR) AF: 1.00 AC: 15298 AN: 15298

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 3468 AN: 3468

East Asian (EAS) AF: 1.00 AC: 5102 AN: 5102

South Asian (SAS) AF: 1.00 AC: 4816 AN: 4816

European-Finnish (FIN) AF: 1.00 AC: 10592 AN: 10592

Middle Eastern (MID) AF: 1.00 AC: 292 AN: 292

European-Non Finnish (NFE) AF: 1.00 AC: 67880 AN: 67894

Other (OTH) AF: 1.00 AC: 2106 AN: 2106

Alfa AF: 1.00 Hom.: 13725

Bravo AF: 1.00

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	3.9
DANN	Benign	0.37
PhyloP100		-0.70
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs4808864; hg19: chr19-18980213;