19-8256691-C-G

Position:

• chr19-8256691-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_024552.3(CERS4):​c.593C>G​(p.Pro198Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CERS4 NM_024552.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.03

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]

CERS4 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CERS4	NM_024552.3	c.593C>G	p.Pro198Arg	missense_variant	8/12	ENST00000251363.10	NP_078828.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CERS4	ENST00000251363.10	c.593C>G	p.Pro198Arg	missense_variant	8/12	1	NM_024552.3	ENSP00000251363.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 08, 2022

The c.593C>G (p.P198R) alteration is located in exon 8 (coding exon 6) of the CERS4 gene. This alteration results from a C to G substitution at nucleotide position 593, causing the proline (P) at amino acid position 198 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Uncertain	0.081	D
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.65	D;T;T;D
Eigen	Uncertain	0.28
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.95	D;.;D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.43	T;T;T;T
MetaSVM	Uncertain	0.19	D
MutationAssessor	Benign	1.9	.;L;L;.
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-4.4	D;D;D;D
REVEL	Uncertain	0.48
Sift	Uncertain	0.014	D;D;D;T
Sift4G	Uncertain	0.050	T;T;T;T
Polyphen		1.0	.;D;D;.
Vest4		0.37
MutPred		0.46		.;Gain of MoRF binding (P = 0.0158);Gain of MoRF binding (P = 0.0158);Gain of MoRF binding (P = 0.0158);
MVP		0.62
MPC		0.35
ClinPred		0.99	D
GERP RS		3.5
Varity_R		0.69
gMVP		0.69

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: rs775358818; hg19: chr19-8321575;