15-100455661-A-T

Variant names:

• chr15-100455661-A-T
• rs12592841
• NM_001378789.1:c.999+232T>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001378789.1(CERS3):​c.999+232T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.193 in 152,130 control chromosomes in the GnomAD database, including 3,322 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.19 (3322 hom., cov: 33)
• Consequence: CERS3 NM_001378789.1 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.65
• Publications: 1 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BP6: Variant 15-100455661-A-T is Benign according to our data. Variant chr15-100455661-A-T is described in ClinVar as Benign. ClinVar VariationId is 1269421.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.307 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.999+232T>A		intron	N/A	NP_001365718.1	Q8IU89
	CERS3	NM_001290341.2		c.1032+232T>A		intron	N/A	NP_001277270.1	Q8IU89
	CERS3	NM_001290342.2		c.999+232T>A		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.999+232T>A		intron	N/A	ENSP00000506641.1	Q8IU89
	CERS3	ENST00000284382.8	TSL:1	c.999+232T>A		intron	N/A	ENSP00000284382.4	Q8IU89
	CERS3	ENST00000394113.5	TSL:1	c.999+232T>A		intron	N/A	ENSP00000377672.3	Q8IU89

Frequencies

GnomAD3 genomes AF: 0.192 AC: 29260 AN: 152010 Hom.: 3296 Cov.: 33

Gnomad AFR AF: 0.265

Gnomad AMI AF: 0.0725

Gnomad AMR AF: 0.313

Gnomad ASJ AF: 0.147

Gnomad EAS AF: 0.176

Gnomad SAS AF: 0.154

Gnomad FIN AF: 0.181

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.132

Gnomad OTH AF: 0.155

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

GnomAD4 genome AF: 0.193 AC: 29343 AN: 152130 Hom.: 3322 Cov.: 33 AF XY: 0.196 AC XY: 14546 AN XY: 74402

African (AFR) AF: 0.266 AC: 11036 AN: 41490

American (AMR) AF: 0.314 AC: 4797 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.147 AC: 511 AN: 3466

East Asian (EAS) AF: 0.176 AC: 911 AN: 5186

South Asian (SAS) AF: 0.155 AC: 747 AN: 4818

European-Finnish (FIN) AF: 0.181 AC: 1912 AN: 10576

Middle Eastern (MID) AF: 0.116 AC: 34 AN: 294

European-Non Finnish (NFE) AF: 0.132 AC: 8998 AN: 67998

Other (OTH) AF: 0.157 AC: 331 AN: 2112

Alfa AF: 0.0804 Hom.: 94

Bravo AF: 0.206

Asia WGS AF: 0.179 AC: 624 AN: 3464

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.068
DANN	Benign	0.20
PhyloP100		-1.7
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: rs12592841; hg19: chr15-100995866;