15-100456011-T-C

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.881A>G(p.His294Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00487 in 1,612,150 control chromosomes in the GnomAD database, including 176 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0082 (23 hom., cov: 32)
  • Exomes 𝑓: 0.0045 (153 hom.)
• Consequence: CERS3 NM_001378789.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.15

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 (MetaRNN=0.004370272).
• BP6: Variant 15-100456011-T-C is Benign according to our data. Variant chr15-100456011-T-C is described in ClinVar as [Benign]. Clinvar id is 1178503.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0591 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CERS3	NM_001378789.1	c.881A>G	p.His294Arg	missense_variant	11/12	ENST00000679737.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CERS3	ENST00000679737.1	c.881A>G	p.His294Arg	missense_variant	11/12		NM_001378789.1	P1

Frequencies

GnomAD3 genomes AF: 0.00807 AC: 1228 AN: 152110 Hom.: 21 Cov.: 32

Gnomad AFR AF: 0.00490

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0484

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.0117

Gnomad SAS AF: 0.0236

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00119

Gnomad OTH AF: 0.0110

GnomAD3 exomes AF: 0.0136 AC: 3246 AN: 238746 Hom.: 88 AF XY: 0.0125 AC XY: 1611 AN XY: 129282

Gnomad AFR exome AF: 0.00535

Gnomad AMR exome AF: 0.0667

Gnomad ASJ exome AF: 0.00137

Gnomad EAS exome AF: 0.0105

Gnomad SAS exome AF: 0.0243

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000979

Gnomad OTH exome AF: 0.0143

GnomAD4 exome AF: 0.00453 AC: 6611 AN: 1459922 Hom.: 153 Cov.: 30 AF XY: 0.00483 AC XY: 3506 AN XY: 726264

Gnomad4 AFR exome AF: 0.00381

Gnomad4 AMR exome AF: 0.0610

Gnomad4 ASJ exome AF: 0.00203

Gnomad4 EAS exome AF: 0.0104

Gnomad4 SAS exome AF: 0.0226

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000798

Gnomad4 OTH exome AF: 0.00706

GnomAD4 genome AF: 0.00818 AC: 1245 AN: 152228 Hom.: 23 Cov.: 32 AF XY: 0.00906 AC XY: 674 AN XY: 74422

Gnomad4 AFR AF: 0.00489

Gnomad4 AMR AF: 0.0491

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.0118

Gnomad4 SAS AF: 0.0236

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00119

Gnomad4 OTH AF: 0.0137

Alfa AF: 0.00254 Hom.: 0

Bravo AF: 0.0102

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.00499 AC: 22

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.0102 AC: 1233

Asia WGS AF: 0.0360 AC: 125 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 11, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.36
Cadd	Benign	19
Dann	Benign	0.88
DEOGEN2	Benign	0.18	T;T;T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.32	N
MetaRNN	Benign	0.0044	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.20	N;N;N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.0	N;N;N
REVEL	Benign	0.24
Sift	Benign	0.32	T;T;T
Sift4G	Benign	0.30	T;T;T
Polyphen		0.0040	B;B;B
Vest4		0.13
MPC		0.16
ClinPred		0.014	T
GERP RS		5.7
Varity_R		0.10
gMVP		0.24

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: rs114065539; hg19: chr15-100996216;