15-100455896-CA-TG

Variant names:

• chr15-100455896-CA-TG
• NM_001378789.1:c.995_996delTGinsCA
• CERS3 p.Met332Thr

Variant summary

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

The NM_001378789.1(CERS3):​c.995_996delTGinsCA​(p.Met332Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CERS3 NM_001378789.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.930
• 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: Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)
• congenital non-bullous ichthyosiform erythroderma

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

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.995_996delTGinsCA	p.Met332Thr	missense	N/A	NP_001365718.1	Q8IU89
	CERS3	NM_001290341.2		c.1028_1029delTGinsCA	p.Met343Thr	missense	N/A	NP_001277270.1	Q8IU89
	CERS3	NM_001290342.2		c.995_996delTGinsCA	p.Met332Thr	missense	N/A	NP_001277271.1	Q8IU89

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CERS3	ENST00000679737.1	MANE Select	c.995_996delTGinsCA	p.Met332Thr	missense	N/A	ENSP00000506641.1	Q8IU89
	CERS3	ENST00000284382.8	TSL:1	c.995_996delTGinsCA	p.Met332Thr	missense	N/A	ENSP00000284382.4	Q8IU89
	CERS3	ENST00000394113.5	TSL:1	c.995_996delTGinsCA	p.Met332Thr	missense	N/A	ENSP00000377672.3	Q8IU89

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.93

Splicing

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

hg19: chr15-100996101;