chr15-100455871-AT-A

Variant names:

• chr15-100455871-AT-A
• rs11323964
• NM_001378789.1:c.999+21delA

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_001378789.1(CERS3):​c.999+21delA variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.30 (7182 hom., cov: 0)
  • Exomes 𝑓: 0.33 (77118 hom.)
• Consequence: CERS3 NM_001378789.1 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.669
• 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), G2P, Genomics England PanelApp
• congenital non-bullous ichthyosiform erythroderma

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP6: Variant 15-100455871-AT-A is Benign according to our data. Variant chr15-100455871-AT-A is described in ClinVar as Benign. ClinVar VariationId is 1282233.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.41 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+21delA		intron	N/A	NP_001365718.1	Q8IU89
	CERS3	NM_001290341.2		c.1032+21delA		intron	N/A	NP_001277270.1	Q8IU89
	CERS3	NM_001290342.2		c.999+21delA		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+21delA		intron	N/A	ENSP00000506641.1	Q8IU89
	CERS3	ENST00000284382.8	TSL:1	c.999+21delA		intron	N/A	ENSP00000284382.4	Q8IU89
	CERS3	ENST00000394113.5	TSL:1	c.999+21delA		intron	N/A	ENSP00000377672.3	Q8IU89

Frequencies

GnomAD3 genomes AF: 0.302 AC: 45915 AN: 151900 Hom.: 7174 Cov.: 0

Gnomad AFR AF: 0.265

Gnomad AMI AF: 0.377

Gnomad AMR AF: 0.228

Gnomad ASJ AF: 0.335

Gnomad EAS AF: 0.425

Gnomad SAS AF: 0.418

Gnomad FIN AF: 0.294

Gnomad MID AF: 0.339

Gnomad NFE AF: 0.323

Gnomad OTH AF: 0.301

GnomAD2 exomes AF: 0.317 AC: 69210 AN: 217992 AF XY: 0.328

Gnomad AFR exome AF: 0.259

Gnomad AMR exome AF: 0.171

Gnomad ASJ exome AF: 0.340

Gnomad EAS exome AF: 0.437

Gnomad FIN exome AF: 0.303

Gnomad NFE exome AF: 0.321

Gnomad OTH exome AF: 0.310

GnomAD4 exome AF: 0.328 AC: 458141 AN: 1394822 Hom.: 77118 Cov.: 0 AF XY: 0.331 AC XY: 229707 AN XY: 693224

African (AFR) AF: 0.259 AC: 7877 AN: 30464

American (AMR) AF: 0.180 AC: 6646 AN: 37008

Ashkenazi Jewish (ASJ) AF: 0.329 AC: 8042 AN: 24460

East Asian (EAS) AF: 0.408 AC: 15140 AN: 37134

South Asian (SAS) AF: 0.414 AC: 31657 AN: 76492

European-Finnish (FIN) AF: 0.308 AC: 15959 AN: 51742

Middle Eastern (MID) AF: 0.329 AC: 1822 AN: 5544

European-Non Finnish (NFE) AF: 0.327 AC: 351737 AN: 1074396

Other (OTH) AF: 0.334 AC: 19261 AN: 57582

GnomAD4 genome AF: 0.302 AC: 45949 AN: 152018 Hom.: 7182 Cov.: 0 AF XY: 0.303 AC XY: 22504 AN XY: 74318

African (AFR) AF: 0.265 AC: 10983 AN: 41456

American (AMR) AF: 0.228 AC: 3481 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.335 AC: 1162 AN: 3464

East Asian (EAS) AF: 0.425 AC: 2189 AN: 5154

South Asian (SAS) AF: 0.418 AC: 2011 AN: 4810

European-Finnish (FIN) AF: 0.294 AC: 3108 AN: 10574

Middle Eastern (MID) AF: 0.344 AC: 101 AN: 294

European-Non Finnish (NFE) AF: 0.323 AC: 21926 AN: 67964

Other (OTH) AF: 0.306 AC: 645 AN: 2110

Alfa AF: 0.212 Hom.: 692

Bravo AF: 0.293

Asia WGS AF: 0.412 AC: 1431 AN: 3478

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
PhyloP100		-0.67
Mutation Taster		=95/5	polymorphism

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: rs11323964; hg19: chr15-100996076; COSMIC: COSV107316945;