NM_001378789.1:c.999+173T>C

Variant names:

• chr15-100455720-A-G
• rs12050655
• NM_001378789.1:c.999+173T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001378789.1(CERS3):​c.999+173T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.492 in 151,940 control chromosomes in the GnomAD database, including 18,763 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.49 (18763 hom., cov: 32)
• Consequence: CERS3 NM_001378789.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.37
• Publications: 3 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 15-100455720-A-G is Benign according to our data. Variant chr15-100455720-A-G is described in ClinVar as Benign. ClinVar VariationId is 1221617.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.54 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+173T>C		intron	N/A	NP_001365718.1	Q8IU89
	CERS3	NM_001290341.2		c.1032+173T>C		intron	N/A	NP_001277270.1	Q8IU89
	CERS3	NM_001290342.2		c.999+173T>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.999+173T>C		intron	N/A	ENSP00000506641.1	Q8IU89
	CERS3	ENST00000284382.8	TSL:1	c.999+173T>C		intron	N/A	ENSP00000284382.4	Q8IU89
	CERS3	ENST00000394113.5	TSL:1	c.999+173T>C		intron	N/A	ENSP00000377672.3	Q8IU89

Frequencies

GnomAD3 genomes AF: 0.493 AC: 74791 AN: 151822 Hom.: 18773 Cov.: 32

Gnomad AFR AF: 0.427

Gnomad AMI AF: 0.549

Gnomad AMR AF: 0.454

Gnomad ASJ AF: 0.517

Gnomad EAS AF: 0.399

Gnomad SAS AF: 0.429

Gnomad FIN AF: 0.523

Gnomad MID AF: 0.547

Gnomad NFE AF: 0.545

Gnomad OTH AF: 0.533

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

GnomAD4 genome AF: 0.492 AC: 74791 AN: 151940 Hom.: 18763 Cov.: 32 AF XY: 0.489 AC XY: 36335 AN XY: 74274

African (AFR) AF: 0.427 AC: 17688 AN: 41446

American (AMR) AF: 0.453 AC: 6922 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.517 AC: 1794 AN: 3470

East Asian (EAS) AF: 0.399 AC: 2065 AN: 5174

South Asian (SAS) AF: 0.427 AC: 2057 AN: 4812

European-Finnish (FIN) AF: 0.523 AC: 5503 AN: 10526

Middle Eastern (MID) AF: 0.541 AC: 159 AN: 294

European-Non Finnish (NFE) AF: 0.545 AC: 36991 AN: 67932

Other (OTH) AF: 0.527 AC: 1112 AN: 2112

Alfa AF: 0.496 Hom.: 3073

Bravo AF: 0.487

Asia WGS AF: 0.408 AC: 1414 AN: 3470

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	14
DANN	Benign	0.91
PhyloP100		1.4
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: rs12050655; hg19: chr15-100995925; COSMIC: COSV52573362;