chr15-100468370-A-G

Variant names:

• chr15-100468370-A-G
• rs8029244
• NM_001378789.1:c.845+1008T>C

Variant summary

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

The NM_001378789.1(CERS3):​c.845+1008T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.431 in 151,944 control chromosomes in the GnomAD database, including 14,826 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 0.43 (14826 hom., cov: 31)
• Consequence: CERS3 NM_001378789.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.828
• Publications: 4 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), Genomics England PanelApp, G2P, PanelApp Australia
• 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=-0.91).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.5 is higher than 0.05.

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.845+1008T>C		intron	N/A	NP_001365718.1	Q8IU89
	CERS3	NM_001290341.2		c.878+1008T>C		intron	N/A	NP_001277270.1	Q8IU89
	CERS3	NM_001290342.2		c.845+1008T>C		intron	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.845+1008T>C		intron	N/A	ENSP00000506641.1	Q8IU89
	CERS3	ENST00000284382.8	TSL:1	c.845+1008T>C		intron	N/A	ENSP00000284382.4	Q8IU89
	CERS3	ENST00000394113.5	TSL:1	c.845+1008T>C		intron	N/A	ENSP00000377672.3	Q8IU89

Frequencies

GnomAD3 genomes AF: 0.432 AC: 65579 AN: 151826 Hom.: 14843 Cov.: 31

Gnomad AFR AF: 0.297

Gnomad AMI AF: 0.482

Gnomad AMR AF: 0.411

Gnomad ASJ AF: 0.492

Gnomad EAS AF: 0.418

Gnomad SAS AF: 0.429

Gnomad FIN AF: 0.496

Gnomad MID AF: 0.528

Gnomad NFE AF: 0.505

Gnomad OTH AF: 0.474

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

GnomAD4 genome AF: 0.431 AC: 65561 AN: 151944 Hom.: 14826 Cov.: 31 AF XY: 0.431 AC XY: 31994 AN XY: 74262

African (AFR) AF: 0.297 AC: 12292 AN: 41450

American (AMR) AF: 0.411 AC: 6268 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.492 AC: 1705 AN: 3468

East Asian (EAS) AF: 0.418 AC: 2154 AN: 5156

South Asian (SAS) AF: 0.427 AC: 2054 AN: 4810

European-Finnish (FIN) AF: 0.496 AC: 5233 AN: 10546

Middle Eastern (MID) AF: 0.527 AC: 155 AN: 294

European-Non Finnish (NFE) AF: 0.505 AC: 34274 AN: 67936

Other (OTH) AF: 0.469 AC: 987 AN: 2106

Alfa AF: 0.435 Hom.: 5989

Bravo AF: 0.421

Asia WGS AF: 0.408 AC: 1418 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.41
DANN	Benign	0.30
PhyloP100		-0.83
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: rs8029244; hg19: chr15-101008575;