19-8261982-C-T

Variant names:

• chr19-8261982-C-T
• rs17160348
• NM_024552.3:c.1058C>T

Variant summary

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

The NM_024552.3(CERS4):​c.1058C>T​(p.Ala353Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.157 in 1,597,496 control chromosomes in the GnomAD database, including 20,549 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 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 the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.15 (1727 hom., cov: 32)
  • Exomes 𝑓: 0.16 (18822 hom.)
• Consequence: CERS4 NM_024552.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.05

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=0.0060577095).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.174 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CERS4	NM_024552.3	c.1058C>T	p.Ala353Val	missense_variant	Exon 12 of 12	ENST00000251363.10	NP_078828.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CERS4	ENST00000251363.10	c.1058C>T	p.Ala353Val	missense_variant	Exon 12 of 12	1	NM_024552.3	ENSP00000251363.5

Frequencies

GnomAD3 genomes AF: 0.148 AC: 22440 AN: 152134 Hom.: 1725 Cov.: 32

Gnomad AFR AF: 0.129

Gnomad AMI AF: 0.0724

Gnomad AMR AF: 0.179

Gnomad ASJ AF: 0.146

Gnomad EAS AF: 0.0835

Gnomad SAS AF: 0.114

Gnomad FIN AF: 0.141

Gnomad MID AF: 0.215

Gnomad NFE AF: 0.160

Gnomad OTH AF: 0.158

GnomAD3 exomes AF: 0.161 AC: 38242 AN: 236862 Hom.: 3561 AF XY: 0.156 AC XY: 20054 AN XY: 128422

Gnomad AFR exome AF: 0.133

Gnomad AMR exome AF: 0.276

Gnomad ASJ exome AF: 0.154

Gnomad EAS exome AF: 0.0794

Gnomad SAS exome AF: 0.128

Gnomad FIN exome AF: 0.145

Gnomad NFE exome AF: 0.159

Gnomad OTH exome AF: 0.153

GnomAD4 exome AF: 0.158 AC: 228090 AN: 1445244 Hom.: 18822 Cov.: 31 AF XY: 0.157 AC XY: 112625 AN XY: 717920

Gnomad4 AFR exome AF: 0.133

Gnomad4 AMR exome AF: 0.258

Gnomad4 ASJ exome AF: 0.149

Gnomad4 EAS exome AF: 0.0810

Gnomad4 SAS exome AF: 0.129

Gnomad4 FIN exome AF: 0.145

Gnomad4 NFE exome AF: 0.161

Gnomad4 OTH exome AF: 0.154

GnomAD4 genome AF: 0.147 AC: 22446 AN: 152252 Hom.: 1727 Cov.: 32 AF XY: 0.144 AC XY: 10743 AN XY: 74448

Gnomad4 AFR AF: 0.129

Gnomad4 AMR AF: 0.179

Gnomad4 ASJ AF: 0.146

Gnomad4 EAS AF: 0.0835

Gnomad4 SAS AF: 0.113

Gnomad4 FIN AF: 0.141

Gnomad4 NFE AF: 0.160

Gnomad4 OTH AF: 0.155

Alfa AF: 0.154 Hom.: 4524

Bravo AF: 0.153

TwinsUK AF: 0.164 AC: 608

ALSPAC AF: 0.160 AC: 615

ESP6500AA AF: 0.134 AC: 589

ESP6500EA AF: 0.164 AC: 1411

ExAC AF: 0.157 AC: 19080

Asia WGS AF: 0.0990 AC: 342 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	13
DANN	Uncertain	0.99
DEOGEN2	Benign	0.10	T;T;T;T
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.40	N
LIST_S2	Benign	0.25	T;.;T;T
MetaRNN	Benign	0.0061	T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.69	.;N;N;.
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.73	N;N;N;N
REVEL	Benign	0.064
Sift	Benign	0.20	T;T;T;T
Sift4G	Benign	0.27	T;T;T;T
Polyphen		0.0010	.;B;B;.
Vest4		0.061
MPC		0.053
ClinPred		0.017	T
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.015
gMVP		0.26

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: rs17160348; hg19: chr19-8326866; COSMIC: COSV52168747; COSMIC: COSV52168747;