rs1041161328

Positions:

• chr19-18896057-G-C
• chr19-18896057-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_021267.5(CERS1):​c.16C>G​(p.Pro6Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P6T) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 30)
• Consequence: CERS1 NM_021267.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.47

Genes affected

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]

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04512465).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CERS1	NM_021267.5	c.16C>G	p.Pro6Ala	missense_variant	1/8	ENST00000623882.4
GDF1	NM_001492.6	c.-1307C>G		5_prime_UTR_variant	1/8	ENST00000247005.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CERS1	ENST00000623882.4	c.16C>G	p.Pro6Ala	missense_variant	1/8	1	NM_021267.5	P2
CERS1	ENST00000429504.6	c.16C>G	p.Pro6Ala	missense_variant	1/6	1		A2
GDF1	ENST00000247005.8	c.-1307C>G		5_prime_UTR_variant	1/8	1	NM_001492.6	P1
CERS1	ENST00000542296.6	c.-46+504C>G		intron_variant		1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 23

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.051
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	0.29
DANN	Benign	0.69
DEOGEN2	Benign	0.30	T;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.25	T;T
M_CAP	Benign	0.0069	T
MetaRNN	Benign	0.045	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-0.26	N;N
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.34	.;N
REVEL	Benign	0.024
Sift	Benign	0.68	.;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;.
Vest4		0.065
MutPred		0.15		Gain of helix (P = 0.0093);Gain of helix (P = 0.0093);
MVP		0.030
ClinPred		0.035	T
GERP RS		-5.8
Varity_R		0.018

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-19006866;