chr19-18895895-G-T

Variant names:

• chr19-18895895-G-T
• rs760185006
• NM_001492.6:c.-1145C>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001492.6(GDF1):​c.-1145C>A 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 0.000000898 in 1,113,584 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 9.0e-7 (0 hom.)
• Consequence: GDF1 NM_001492.6 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.855
• 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: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28177226).

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.-1145C>A		5_prime_UTR_premature_start_codon_gain	Exon 1 of 8	NP_001483.3
	CERS1	NM_021267.5	MANE Select	c.178C>A	p.Leu60Met	missense	Exon 1 of 8	NP_067090.1
	GDF1	NM_001492.6	MANE Select	c.-1145C>A		5_prime_UTR	Exon 1 of 8	NP_001483.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GDF1	ENST00000247005.8	TSL:1 MANE Select	c.-1145C>A		5_prime_UTR_premature_start_codon_gain	Exon 1 of 8	ENSP00000247005.5
	CERS1	ENST00000623882.4	TSL:1 MANE Select	c.178C>A	p.Leu60Met	missense	Exon 1 of 8	ENSP00000485308.1
	CERS1	ENST00000429504.6	TSL:1	c.178C>A	p.Leu60Met	missense	Exon 1 of 6	ENSP00000389044.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 8.98e-7 AC: 1 AN: 1113584 Hom.: 0 Cov.: 32 AF XY: 0.00000185 AC XY: 1 AN XY: 540762

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 21254

American (AMR) AF: 0.00 AC: 0 AN: 8642

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13444

East Asian (EAS) AF: 0.00 AC: 0 AN: 23230

South Asian (SAS) AF: 0.0000248 AC: 1 AN: 40308

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 23260

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2836

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 937426

Other (OTH) AF: 0.00 AC: 0 AN: 43184

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.43	T
Eigen	Benign	0.071
Eigen_PC	Benign	-0.0046
FATHMM_MKL	Benign	0.46	N
LIST_S2	Benign	0.38	T
M_CAP	Pathogenic	0.50	D
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L
PhyloP100		0.85
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-0.63	N
REVEL	Benign	0.071
Sift	Benign	0.086	T
Sift4G	Benign	0.068	T
Polyphen		0.95	P
Vest4		0.20
MutPred		0.42		Gain of loop (P = 0.2045)
MVP		0.53
ClinPred		0.75	D
GERP RS		2.1
PromoterAI		-0.29	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.19
Mutation Taster		=85/15	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: rs760185006; hg19: chr19-19006704;