rs36259

Positions:

• chr19-8262020-G-A
• chr19-8262020-G-C
• chr19-8262020-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_024552.3(CERS4):​c.1096G>A​(p.Ala366Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.757 in 1,583,458 control chromosomes in the GnomAD database, including 454,121 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.74 (42222 hom., cov: 35)
  • Exomes 𝑓: 0.76 (411899 hom.)
• Consequence: CERS4 NM_024552.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.970

Genes affected

CERS4 (HGNC:23747): (ceramide synthase 4) Enables sphingosine N-acyltransferase activity. Involved in ceramide biosynthetic process. Predicted to be located in endoplasmic reticulum membrane. Predicted to be active in endoplasmic reticulum. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.0931072E-6).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.78 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CERS4	NM_024552.3	c.1096G>A	p.Ala366Thr	missense_variant	12/12	ENST00000251363.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CERS4	ENST00000251363.10	c.1096G>A	p.Ala366Thr	missense_variant	12/12	1	NM_024552.3	P1

Frequencies

GnomAD3 genomes AF: 0.743 AC: 113077 AN: 152124 Hom.: 42191 Cov.: 35

Gnomad AFR AF: 0.683

Gnomad AMI AF: 0.896

Gnomad AMR AF: 0.770

Gnomad ASJ AF: 0.812

Gnomad EAS AF: 0.800

Gnomad SAS AF: 0.757

Gnomad FIN AF: 0.754

Gnomad MID AF: 0.722

Gnomad NFE AF: 0.761

Gnomad OTH AF: 0.765

GnomAD3 exomes AF: 0.750 AC: 166419 AN: 221872 Hom.: 62608 AF XY: 0.753 AC XY: 90900 AN XY: 120758

Gnomad AFR exome AF: 0.682

Gnomad AMR exome AF: 0.700

Gnomad ASJ exome AF: 0.810

Gnomad EAS exome AF: 0.801

Gnomad SAS exome AF: 0.743

Gnomad FIN exome AF: 0.748

Gnomad NFE exome AF: 0.762

Gnomad OTH exome AF: 0.775

GnomAD4 exome AF: 0.758 AC: 1085015 AN: 1431214 Hom.: 411899 Cov.: 75 AF XY: 0.758 AC XY: 538264 AN XY: 710280

Gnomad4 AFR exome AF: 0.670

Gnomad4 AMR exome AF: 0.712

Gnomad4 ASJ exome AF: 0.809

Gnomad4 EAS exome AF: 0.814

Gnomad4 SAS exome AF: 0.736

Gnomad4 FIN exome AF: 0.745

Gnomad4 NFE exome AF: 0.761

Gnomad4 OTH exome AF: 0.764

GnomAD4 genome AF: 0.743 AC: 113161 AN: 152244 Hom.: 42222 Cov.: 35 AF XY: 0.746 AC XY: 55509 AN XY: 74430

Gnomad4 AFR AF: 0.683

Gnomad4 AMR AF: 0.770

Gnomad4 ASJ AF: 0.812

Gnomad4 EAS AF: 0.800

Gnomad4 SAS AF: 0.757

Gnomad4 FIN AF: 0.754

Gnomad4 NFE AF: 0.761

Gnomad4 OTH AF: 0.770

Alfa AF: 0.761 Hom.: 100381

Bravo AF: 0.741

TwinsUK AF: 0.755 AC: 2800

ALSPAC AF: 0.765 AC: 2947

ESP6500AA AF: 0.690 AC: 3039

ESP6500EA AF: 0.765 AC: 6572

ExAC AF: 0.744 AC: 90078

Asia WGS AF: 0.775 AC: 2695 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	7.5
DANN	Benign	0.71
DEOGEN2	Benign	0.089	T;T;T;T
Eigen	Benign	-0.94
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.048	N
LIST_S2	Benign	0.51	T;.;T;T
MetaRNN	Benign	0.0000011	T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	2.0	.;M;M;.
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.21	N;N;N;N
REVEL	Benign	0.063
Sift	Benign	0.58	T;T;T;D
Sift4G	Benign	0.59	T;T;T;T
Polyphen		0.012	.;B;B;.
Vest4		0.088
MPC		0.060
ClinPred		0.0041	T
GERP RS		0.91
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.048
gMVP		0.17

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: rs36259; hg19: chr19-8326904; COSMIC: COSV52167244; COSMIC: COSV52167244;