15-100455928-T-G

Variant names:

• chr15-100455928-T-G
• rs2034353881
• NM_001378789.1:c.964A>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001378789.1(CERS3):​c.964A>C​(p.Ile322Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,460,110 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. I322V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: CERS3 NM_001378789.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.25
• Publications: 0 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: Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp
• congenital non-bullous ichthyosiform erythroderma

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001378789.1. 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
	CERS3	NM_001378789.1	MANE Select	c.964A>C	p.Ile322Leu	missense	Exon 11 of 12	NP_001365718.1	Q8IU89
	CERS3	NM_001290341.2		c.997A>C	p.Ile333Leu	missense	Exon 13 of 14	NP_001277270.1	Q8IU89
	CERS3	NM_001290342.2		c.964A>C	p.Ile322Leu	missense	Exon 12 of 13	NP_001277271.1	Q8IU89

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CERS3	ENST00000679737.1	MANE Select	c.964A>C	p.Ile322Leu	missense	Exon 11 of 12	ENSP00000506641.1	Q8IU89
	CERS3	ENST00000284382.8	TSL:1	c.964A>C	p.Ile322Leu	missense	Exon 12 of 13	ENSP00000284382.4	Q8IU89
	CERS3	ENST00000394113.5	TSL:1	c.964A>C	p.Ile322Leu	missense	Exon 13 of 14	ENSP00000377672.3	Q8IU89

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000130 AC: 19 AN: 1460110 Hom.: 0 Cov.: 30 AF XY: 0.0000138 AC XY: 10 AN XY: 726438

African (AFR) AF: 0.00 AC: 0 AN: 33364

American (AMR) AF: 0.00 AC: 0 AN: 44378

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26096

East Asian (EAS) AF: 0.00 AC: 0 AN: 39584

South Asian (SAS) AF: 0.00 AC: 0 AN: 86072

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53362

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.0000162 AC: 18 AN: 1111180

Other (OTH) AF: 0.0000166 AC: 1 AN: 60318

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.53	D
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.081	D
MetaRNN	Uncertain	0.52	D
MetaSVM	Uncertain	0.41	D
MutationAssessor	Pathogenic	3.4	M
PhyloP100		3.2
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.64
Sift	Benign	0.030	D
Sift4G	Uncertain	0.0070	D
Polyphen		0.58	P
Vest4		0.44
MutPred		0.74		Loss of methylation at K324 (P = 0.0478)
MVP		0.59
MPC		0.27
ClinPred		0.96	D
GERP RS		4.2
Varity_R		0.20
gMVP		0.64
Mutation Taster		=86/14	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: rs2034353881; hg19: chr15-100996133;