rs1041161328

Variant names:

• chr19-18896057-G-T
• rs1041161328
• NM_021267.5:c.16C>A
• CERS1 p.Pro6Thr

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_021267.5(CERS1):​c.16C>A​(p.Pro6Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000146 in 982,440 control chromosomes in the GnomAD database, with no homozygous occurrence. 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P6R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00064 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000060 (0 hom.)
• Consequence: CERS1 NM_021267.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: -1.47
• Publications: 0 publications found

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]

GDF1 Gene-Disease associations (from GenCC):

• right atrial isomerism

  Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet
• congenital heart defects, multiple types, 6

  Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: Ambry Genetics, Illumina
• conotruncal heart malformations

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.02537322).
• BP6: Variant 19-18896057-G-T is Benign according to our data. Variant chr19-18896057-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 542128.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021267.5. 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
	CERS1	NM_021267.5	MANE Select	c.16C>A	p.Pro6Thr	missense	Exon 1 of 8	NP_067090.1	P27544-1
	GDF1	NM_001492.6	MANE Select	c.-1307C>A		5_prime_UTR	Exon 1 of 8	NP_001483.3
	CERS1	NM_001387439.1		c.16C>A	p.Pro6Thr	missense	Exon 1 of 7	NP_001374368.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CERS1	ENST00000623882.4	TSL:1 MANE Select	c.16C>A	p.Pro6Thr	missense	Exon 1 of 8	ENSP00000485308.1	P27544-1
	CERS1	ENST00000429504.6	TSL:1	c.16C>A	p.Pro6Thr	missense	Exon 1 of 6	ENSP00000389044.1	P27544-2
	GDF1	ENST00000247005.8	TSL:1 MANE Select	c.-1307C>A		5_prime_UTR	Exon 1 of 8	ENSP00000247005.5	P27539

Frequencies

GnomAD3 genomes AF: 0.000636 AC: 93 AN: 146138 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00226

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000679

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000598 AC: 50 AN: 836198 Hom.: 0 Cov.: 23 AF XY: 0.0000543 AC XY: 21 AN XY: 386830

African (AFR) AF: 0.00304 AC: 48 AN: 15798

American (AMR) AF: 0.00 AC: 0 AN: 1168

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5242

East Asian (EAS) AF: 0.00 AC: 0 AN: 3792

South Asian (SAS) AF: 0.00 AC: 0 AN: 17116

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 794

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1634

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 763140

Other (OTH) AF: 0.0000727 AC: 2 AN: 27514

GnomAD4 genome AF: 0.000636 AC: 93 AN: 146242 Hom.: 0 Cov.: 30 AF XY: 0.000576 AC XY: 41 AN XY: 71176

African (AFR) AF: 0.00225 AC: 92 AN: 40898

American (AMR) AF: 0.0000678 AC: 1 AN: 14746

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3384

East Asian (EAS) AF: 0.00 AC: 0 AN: 5046

South Asian (SAS) AF: 0.00 AC: 0 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8338

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 65788

Other (OTH) AF: 0.00 AC: 0 AN: 2032

Alfa AF: 0.000498 Hom.: 0

Bravo AF: 0.000740

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.48
DANN	Benign	0.71
DEOGEN2	Benign	0.28	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0084	N
LIST_S2	Benign	0.26	T
M_CAP	Benign	0.0064	T
MetaRNN	Benign	0.025	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.1	L
PhyloP100		-1.5
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-0.25	N
REVEL	Benign	0.016
Sift	Benign	1.0	T
Sift4G	Benign	0.55	T
PromoterAI		-0.051	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.6
Varity_R		0.026
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1041161328;

hg19: chr19-19006866;