rs12438080

Variant names:

• chr15-100541858-A-C
• rs12438080
• ENST00000284382.8:c.-355+2793T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000284382.8(CERS3):​c.-355+2793T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.5 in 151,832 control chromosomes in the GnomAD database, including 19,249 homozygotes. 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: 𝑓 0.50 (19249 hom., cov: 33)
• Consequence: CERS3 ENST00000284382.8 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.823
• Publications: 5 publications found

Genes affected

CERS3 (HGNC:23752): (ceramide synthase 3) This gene is a member of the ceramide synthase family of genes. The ceramide synthase enzymes regulate sphingolipid synthesis by catalyzing the formation of ceramides from sphingoid base and acyl-coA substrates. This family member is involved in the synthesis of ceramides with ultra-long-chain acyl moieties (ULC-Cers), important to the epidermis in its role in creating a protective barrier from the environment. The protein encoded by this gene has also been implicated in modification of the lipid structures required for spermatogenesis. Mutations in this gene have been associated with male fertility defects, and epidermal defects, including ichthyosis. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Aug 2015]

CERS3 Gene-Disease associations (from GenCC):

• autosomal recessive congenital ichthyosis 9

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Genomics England PanelApp, G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• congenital non-bullous ichthyosiform erythroderma

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.577 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CERS3	NM_001290341.2	c.-461+2358T>G		intron_variant	Intron 1 of 13		NP_001277270.1
CERS3	NM_001290342.2	c.-355+2266T>G		intron_variant	Intron 1 of 12		NP_001277271.1
CERS3	NM_001290343.2	c.-355+2789T>G		intron_variant	Intron 1 of 12		NP_001277272.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CERS3	ENST00000284382.8	c.-355+2793T>G		intron_variant	Intron 1 of 12	1		ENSP00000284382.4
CERS3	ENST00000394113.5	c.-494+2358T>G		intron_variant	Intron 1 of 13	1		ENSP00000377672.3
CERS3	ENST00000538112.6	c.-355+2266T>G		intron_variant	Intron 1 of 12	1		ENSP00000437640.2

Frequencies

GnomAD3 genomes AF: 0.500 AC: 75801 AN: 151712 Hom.: 19233 Cov.: 33

Gnomad AFR AF: 0.437

Gnomad AMI AF: 0.486

Gnomad AMR AF: 0.574

Gnomad ASJ AF: 0.451

Gnomad EAS AF: 0.304

Gnomad SAS AF: 0.597

Gnomad FIN AF: 0.587

Gnomad MID AF: 0.475

Gnomad NFE AF: 0.518

Gnomad OTH AF: 0.501

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.500 AC: 75865 AN: 151832 Hom.: 19249 Cov.: 33 AF XY: 0.505 AC XY: 37504 AN XY: 74196

African (AFR) AF: 0.437 AC: 18103 AN: 41420

American (AMR) AF: 0.575 AC: 8762 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.451 AC: 1563 AN: 3466

East Asian (EAS) AF: 0.304 AC: 1575 AN: 5178

South Asian (SAS) AF: 0.595 AC: 2866 AN: 4814

European-Finnish (FIN) AF: 0.587 AC: 6173 AN: 10522

Middle Eastern (MID) AF: 0.463 AC: 136 AN: 294

European-Non Finnish (NFE) AF: 0.518 AC: 35193 AN: 67880

Other (OTH) AF: 0.500 AC: 1056 AN: 2110

Alfa AF: 0.510 Hom.: 4608

Bravo AF: 0.491

Asia WGS AF: 0.475 AC: 1650 AN: 3470

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.4
DANN	Benign	0.52
PhyloP100		-0.82
Mutation Taster		=100/0	polymorphism (auto)

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: rs12438080; hg19: chr15-101082063;