15-100402840-T-C

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

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 the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.016 ( 25 hom., cov: 33)

Exomes 𝑓: 0.021 ( 344 hom. )

Consequence

CERS3
NM_001378789.1 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.0140

Variant links:

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 links:

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

CERS3-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 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_multiple_submitters_no_conflicts, 2 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 GnomAd4 at 25 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CERS3	NM_001378789.1 link	c.1025A>G	p.Asp342Gly	missense_variant	Exon 12 of 12	ENST00000679737.1	NP_001365718.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CERS3	ENST00000679737.1 link	c.1025A>G	p.Asp342Gly	missense_variant	Exon 12 of 12		NM_001378789.1	ENSP00000506641.1		Q8IU89

Frequencies

GnomAD3 genomes

AF:

0.0160

AC:

2442

AN:

152196

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.0178

AC XY:

2273

AN XY:

127800

show subpopulations

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.:

AF XY:

0.0203

AC XY:

14685

AN XY:

723562

show subpopulations

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.:

Cov.:

AF XY:

0.0151

AC XY:

1125

AN XY:

74480

show subpopulations

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.:

Bravo

AF:

0.0155

TwinsUK

AF:

0.0251

AC:

ALSPAC

AF:

0.0208

AC:

ESP6500AA

AF:

0.00272

AC:

ESP6500EA

AF:

0.0228

AC:

196

ExAC

AF:

0.0168

AC:

2040

Asia WGS

AF:

0.00289

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.70

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

LIST_S2

Benign

0.54

.;.;T

MetaRNN

Benign

0.0022

T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

1.7

L;L;L

PrimateAI

Benign

0.31

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over