15-100402840-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001378789.1(CERS3):c.1025A>G(p.Asp342Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0202 in 1,607,906 control chromosomes in the GnomAD database, including 369 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Synonymous variant affecting the same amino acid position (i.e. D342D) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.016 (25 hom., cov: 33)
  • Exomes 𝑓: 0.021 (344 hom.)
• Consequence: CERS3 NM_001378789.1 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0140

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-AS1 (HGNC:51431): (CERS3 antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0021971464).
• BP6: Variant 15-100402840-T-C is Benign according to our data. Variant chr15-100402840-T-C is described in ClinVar as [Benign]. Clinvar id is 1570405.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.016 (2442/152314) while in subpopulation NFE AF= 0.0228 (1554/68030). AF 95% confidence interval is 0.0219. There are 25 homozygotes in gnomad4. There are 1125 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 25 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CERS3	NM_001378789.1	c.1025A>G	p.Asp342Gly	missense_variant	12/12	ENST00000679737.1
CERS3-AS1	NR_120374.1	n.211+2915T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CERS3	ENST00000679737.1	c.1025A>G	p.Asp342Gly	missense_variant	12/12		NM_001378789.1	P1
CERS3-AS1	ENST00000560643.1	n.51+2915T>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.0160 AC: 2442 AN: 152196 Hom.: 25 Cov.: 33

Gnomad AFR AF: 0.00437

Gnomad AMI AF: 0.0175

Gnomad AMR AF: 0.0212

Gnomad ASJ AF: 0.0323

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00539

Gnomad FIN AF: 0.0167

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0229

Gnomad OTH AF: 0.0172

GnomAD3 exomes AF: 0.0173 AC: 4103 AN: 237052 Hom.: 53 AF XY: 0.0178 AC XY: 2273 AN XY: 127800

Gnomad AFR exome AF: 0.00261

Gnomad AMR exome AF: 0.0119

Gnomad ASJ exome AF: 0.0273

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00987

Gnomad FIN exome AF: 0.0191

Gnomad NFE exome AF: 0.0248

Gnomad OTH exome AF: 0.0160

GnomAD4 exome AF: 0.0206 AC: 30053 AN: 1455592 Hom.: 344 Cov.: 33 AF XY: 0.0203 AC XY: 14685 AN XY: 723562

Gnomad4 AFR exome AF: 0.00359

Gnomad4 AMR exome AF: 0.0128

Gnomad4 ASJ exome AF: 0.0288

Gnomad4 EAS exome AF: 0.0000505

Gnomad4 SAS exome AF: 0.00967

Gnomad4 FIN exome AF: 0.0180

Gnomad4 NFE exome AF: 0.0230

Gnomad4 OTH exome AF: 0.0194

GnomAD4 genome AF: 0.0160 AC: 2442 AN: 152314 Hom.: 25 Cov.: 33 AF XY: 0.0151 AC XY: 1125 AN XY: 74480

Gnomad4 AFR AF: 0.00438

Gnomad4 AMR AF: 0.0212

Gnomad4 ASJ AF: 0.0323

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00560

Gnomad4 FIN AF: 0.0167

Gnomad4 NFE AF: 0.0228

Gnomad4 OTH AF: 0.0170

Alfa AF: 0.0218 Hom.: 67

Bravo AF: 0.0155

TwinsUK AF: 0.0251 AC: 93

ALSPAC AF: 0.0208 AC: 80

ESP6500AA AF: 0.00272 AC: 12

ESP6500EA AF: 0.0228 AC: 196

ExAC AF: 0.0168 AC: 2040

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.76
Cadd	Benign	3.5
Dann	Benign	0.61
DEOGEN2	Benign	0.11	T;T;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.027	N
MetaRNN	Benign	0.0022	T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.7	L;L;L
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.6	N;N;N
REVEL	Benign	0.014
Sift	Benign	0.36	T;T;T
Sift4G	Benign	0.34	T;T;T
Polyphen		0.0	B;B;B
Vest4		0.047
MPC		0.12
ClinPred		0.0063	T
GERP RS		-1.2
Varity_R		0.050
gMVP		0.19

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: rs1023783; hg19: chr15-100943045;