rs762679102

Positions:

• chr15-100501807-A-G
• chr15-100501807-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_001378789.1(CERS3):​c.43T>C​(p.Trp15Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 31)
• Consequence: CERS3 NM_001378789.1 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.30

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.986
• PP5: Variant 15-100501807-A-G is Pathogenic according to our data. Variant chr15-100501807-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 64621.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr15-100501807-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CERS3	NM_001378789.1	c.43T>C	p.Trp15Arg	missense_variant	3/12	ENST00000679737.1	NP_001365718.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CERS3	ENST00000679737.1	c.43T>C	p.Trp15Arg	missense_variant	3/12		NM_001378789.1	ENSP00000506641.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Autosomal recessive congenital ichthyosis 9 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 01, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.53	D;D;D;D;.
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.66
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.63	.;.;T;T;.
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D
MetaSVM	Uncertain	0.64	D
MutationAssessor	Pathogenic	3.6	H;H;H;.;.
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-13	D;D;D;D;D
REVEL	Pathogenic	0.74
Sift	Pathogenic	0.0	D;D;D;D;.
Sift4G	Pathogenic	0.0	D;D;D;.;.
Polyphen		1.0	D;D;D;.;.
Vest4		0.99
MutPred		0.91		Loss of catalytic residue at P18 (P = 0.0338);Loss of catalytic residue at P18 (P = 0.0338);Loss of catalytic residue at P18 (P = 0.0338);Loss of catalytic residue at P18 (P = 0.0338);Loss of catalytic residue at P18 (P = 0.0338);
MVP		0.69
MPC		0.65
ClinPred		1.0	D
GERP RS		4.0
Varity_R		0.88
gMVP		0.99

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

Publications

LitVar

Other links and lift over

dbSNP: rs762679102; hg19: chr15-101042012;