rs370986101

Variant names:

• chr19-18870253-G-C
• rs370986101
• NM_001492.6:c.55C>G

Your query was ambiguous. Multiple possible variants found:

• chr19-18870253-G-C
• chr19-18870253-G-A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001492.6(GDF1):​c.55C>G​(p.Leu19Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000227 in 1,551,400 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0011 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00013 (1 hom.)
• Consequence: GDF1 NM_001492.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:4
• Conservation: PhyloP100: -0.758
• 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013957262).
• BP6: Variant 19-18870253-G-C is Benign according to our data. Variant chr19-18870253-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 258162.
• BS2: High Homozygotes in GnomAd4 at 3 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.55C>G	p.Leu19Val	missense	Exon 7 of 8	NP_001483.3
	CERS1	NM_021267.5	MANE Select	c.*324C>G		3_prime_UTR	Exon 7 of 8	NP_067090.1	P27544-1
	GDF1	NM_001387438.1		c.55C>G	p.Leu19Val	missense	Exon 4 of 5	NP_001374367.1	P27539

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GDF1	ENST00000247005.8	TSL:1 MANE Select	c.55C>G	p.Leu19Val	missense	Exon 7 of 8	ENSP00000247005.5	P27539
	CERS1	ENST00000623882.4	TSL:1 MANE Select	c.*324C>G		3_prime_UTR	Exon 7 of 8	ENSP00000485308.1	P27544-1

Frequencies

GnomAD3 genomes AF: 0.00114 AC: 172 AN: 150676 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00401

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000396

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00333

Gnomad NFE AF: 0.0000148

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000297 AC: 44 AN: 147950 AF XY: 0.000210

Gnomad AFR exome AF: 0.00385

Gnomad AMR exome AF: 0.000526

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000179

Gnomad OTH exome AF: 0.000235

GnomAD4 exome AF: 0.000129 AC: 180 AN: 1400598 Hom.: 1 Cov.: 33 AF XY: 0.000111 AC XY: 77 AN XY: 691832

African (AFR) AF: 0.00402 AC: 129 AN: 32122

American (AMR) AF: 0.000557 AC: 20 AN: 35914

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25170

East Asian (EAS) AF: 0.00 AC: 0 AN: 37068

South Asian (SAS) AF: 0.0000125 AC: 1 AN: 79906

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44704

Middle Eastern (MID) AF: 0.000710 AC: 3 AN: 4228

European-Non Finnish (NFE) AF: 0.00000554 AC: 6 AN: 1083334

Other (OTH) AF: 0.000361 AC: 21 AN: 58152

GnomAD4 genome AF: 0.00114 AC: 172 AN: 150802 Hom.: 3 Cov.: 32 AF XY: 0.00111 AC XY: 82 AN XY: 73678

African (AFR) AF: 0.00400 AC: 164 AN: 41030

American (AMR) AF: 0.000396 AC: 6 AN: 15156

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5012

South Asian (SAS) AF: 0.00 AC: 0 AN: 4728

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10474

Middle Eastern (MID) AF: 0.00350 AC: 1 AN: 286

European-Non Finnish (NFE) AF: 0.0000148 AC: 1 AN: 67656

Other (OTH) AF: 0.00 AC: 0 AN: 2100

Alfa AF: 0.000141 Hom.: 0

Bravo AF: 0.00136

ESP6500AA AF: 0.00122 AC: 4

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000180 AC: 19

Asia WGS AF: 0.000289 AC: 1 AN: 3474

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	3	not provided (4)
-	1	1	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	1.2
DANN	Benign	0.69
DEOGEN2	Benign	0.15	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.068	N
LIST_S2	Benign	0.35	T
M_CAP	Pathogenic	0.65	D
MetaRNN	Benign	0.014	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.2	L
PhyloP100		-0.76
PROVEAN	Benign	-0.39	N
REVEL	Benign	0.16
Sift	Benign	0.22	T
Sift4G	Uncertain	0.054	T
Vest4		0.13
MVP		0.13
MPC		0.95
ClinPred		0.0057	T
GERP RS		-1.1
Varity_R		0.041
gMVP		0.30
Mutation Taster		=90/10	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: rs370986101; hg19: chr19-18981062;