15-100402757-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.1108A>G(p.Arg370Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.998 in 1,614,150 control chromosomes in the GnomAD database, including 803,394 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.

• Frequency:
  • Genomes: 𝑓 0.99 (74245 hom., cov: 31)
  • Exomes 𝑓: 1.0 (729149 hom.)
• Consequence: CERS3 NM_001378789.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.13

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.393242E-6).
• BP6: Variant 15-100402757-T-C is Benign according to our data. Variant chr15-100402757-T-C is described in ClinVar as [Benign]. Clinvar id is 1209730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.994 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CERS3	NM_001378789.1	c.1108A>G	p.Arg370Gly	missense_variant	12/12	ENST00000679737.1
CERS3-AS1	NR_120374.1	n.211+2832T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CERS3	ENST00000679737.1	c.1108A>G	p.Arg370Gly	missense_variant	12/12		NM_001378789.1	P1
CERS3-AS1	ENST00000560643.1	n.51+2832T>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.987 AC: 150218 AN: 152148 Hom.: 74185 Cov.: 31

Gnomad AFR AF: 0.956

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.996

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 0.999

Gnomad SAS AF: 1.00

Gnomad FIN AF: 1.00

Gnomad MID AF: 1.00

Gnomad NFE AF: 1.00

Gnomad OTH AF: 0.991

GnomAD3 exomes AF: 0.996 AC: 250560 AN: 251444 Hom.: 124854 AF XY: 0.997 AC XY: 135558 AN XY: 135904

Gnomad AFR exome AF: 0.953

Gnomad AMR exome AF: 0.998

Gnomad ASJ exome AF: 1.00

Gnomad EAS exome AF: 1.00

Gnomad SAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 1.00

Gnomad OTH exome AF: 0.997

GnomAD4 exome AF: 0.999 AC: 1460057 AN: 1461882 Hom.: 729149 Cov.: 52 AF XY: 0.999 AC XY: 726448 AN XY: 727242

Gnomad4 AFR exome AF: 0.957

Gnomad4 AMR exome AF: 0.998

Gnomad4 ASJ exome AF: 1.00

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 1.00

Gnomad4 FIN exome AF: 1.00

Gnomad4 NFE exome AF: 1.00

Gnomad4 OTH exome AF: 0.997

GnomAD4 genome AF: 0.987 AC: 150338 AN: 152268 Hom.: 74245 Cov.: 31 AF XY: 0.988 AC XY: 73542 AN XY: 74452

Gnomad4 AFR AF: 0.956

Gnomad4 AMR AF: 0.996

Gnomad4 ASJ AF: 1.00

Gnomad4 EAS AF: 0.999

Gnomad4 SAS AF: 1.00

Gnomad4 FIN AF: 1.00

Gnomad4 NFE AF: 1.00

Gnomad4 OTH AF: 0.991

Alfa AF: 0.998 Hom.: 145185

Bravo AF: 0.986

TwinsUK AF: 1.00 AC: 3708

ALSPAC AF: 1.00 AC: 3854

ESP6500AA AF: 0.952 AC: 4195

ESP6500EA AF: 1.00 AC: 8599

ExAC AF: 0.996 AC: 120873

Asia WGS AF: 0.996 AC: 3464 AN: 3478

EpiCase AF: 1.00

EpiControl AF: 1.00

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2018	- -

Autosomal recessive congenital ichthyosis 9 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 22, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.049
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.80
Cadd	Benign	13
Dann	Benign	0.75
DEOGEN2	Benign	0.041	T;T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.00046	N
MetaRNN	Benign	0.0000014	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-2.1	N;N;N
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.90	N;N;N
REVEL	Benign	0.018
Sift	Benign	0.49	T;T;T
Sift4G	Benign	0.43	T;T;T
Polyphen		0.0	B;B;B
Vest4		0.040
MPC		0.12
ClinPred		0.00039	T
GERP RS		3.4
Varity_R		0.081
gMVP		0.071

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: rs2439928; hg19: chr15-100942962;