15-100455833-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001378789.1(CERS3):c.999+60G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.676 in 1,074,012 control chromosomes in the GnomAD database, including 246,937 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.69 (36053 hom., cov: 32)
  • Exomes 𝑓: 0.67 (210884 hom.)
• Consequence: CERS3 NM_001378789.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0630

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BP6: Variant 15-100455833-C-T is Benign according to our data. Variant chr15-100455833-C-T is described in ClinVar as [Benign]. Clinvar id is 1209731.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.76 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CERS3	NM_001378789.1	c.999+60G>A		intron_variant		ENST00000679737.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CERS3	ENST00000679737.1	c.999+60G>A		intron_variant			NM_001378789.1	P1

Frequencies

GnomAD3 genomes AF: 0.689 AC: 104339 AN: 151420 Hom.: 36020 Cov.: 32

Gnomad AFR AF: 0.700

Gnomad AMI AF: 0.622

Gnomad AMR AF: 0.772

Gnomad ASJ AF: 0.666

Gnomad EAS AF: 0.580

Gnomad SAS AF: 0.590

Gnomad FIN AF: 0.710

Gnomad MID AF: 0.661

Gnomad NFE AF: 0.678

Gnomad OTH AF: 0.692

GnomAD4 exome AF: 0.674 AC: 621732 AN: 922474 Hom.: 210884 AF XY: 0.670 AC XY: 312897 AN XY: 467172

Gnomad4 AFR exome AF: 0.706

Gnomad4 AMR exome AF: 0.805

Gnomad4 ASJ exome AF: 0.663

Gnomad4 EAS exome AF: 0.591

Gnomad4 SAS exome AF: 0.561

Gnomad4 FIN exome AF: 0.686

Gnomad4 NFE exome AF: 0.680

Gnomad4 OTH exome AF: 0.668

GnomAD4 genome AF: 0.689 AC: 104422 AN: 151538 Hom.: 36053 Cov.: 32 AF XY: 0.689 AC XY: 51015 AN XY: 74002

Gnomad4 AFR AF: 0.700

Gnomad4 AMR AF: 0.772

Gnomad4 ASJ AF: 0.666

Gnomad4 EAS AF: 0.580

Gnomad4 SAS AF: 0.590

Gnomad4 FIN AF: 0.710

Gnomad4 NFE AF: 0.678

Gnomad4 OTH AF: 0.688

Alfa AF: 0.685 Hom.: 9041

Bravo AF: 0.695

Asia WGS AF: 0.586 AC: 2039 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive congenital ichthyosis 9 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 22, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 10, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
Cadd	Benign	0.67
Dann	Benign	0.34

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: rs12595207; hg19: chr15-100996038; COSMIC: COSV52567705;