Genetic Variant NM_024552.3:c.356G>A (chr19-8255671-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_024552.3(CERS4):c.356G>A(p.Arg119Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0331 in 1,612,880 control chromosomes in the GnomAD database, including 2,332 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.074 ( 784 hom., cov: 32)

Exomes 𝑓: 0.029 ( 1548 hom. )

Consequence

CERS4
NM_024552.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.62

Publications

18 publications found

Variant links:

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 links:

ENSG00000303688 (HGNC:):

ENSG00000303688 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0022135377).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.173 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024552.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CERS4	NM_024552.3	MANE Select	c.356G>A	p.Arg119Gln	missense	Exon 5 of 12	NP_078828.2	Q9HA82

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CERS4	ENST00000251363.10	TSL:1 MANE Select	c.356G>A	p.Arg119Gln	missense	Exon 5 of 12	ENSP00000251363.5	Q9HA82
CERS4	ENST00000559336.5	TSL:1	c.356G>A	p.Arg119Gln	missense	Exon 5 of 10	ENSP00000453815.1	H0YN04
CERS4	ENST00000595722.5	TSL:1	n.685G>A		non_coding_transcript_exon	Exon 6 of 13

Frequencies

GnomAD3 genomes

AF:

0.0740

AC:

11258

AN:

152084

Hom.:

784

Cov.:

show subpopulations

Gnomad AFR

AF:

0.177

Gnomad AMI

AF:

0.0308

Gnomad AMR

AF:

0.0485

Gnomad ASJ

AF:

0.00576

Gnomad EAS

AF:

0.147

Gnomad SAS

AF:

0.0465

Gnomad FIN

AF:

0.0819

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.0167

Gnomad OTH

AF:

0.0703

GnomAD2 exomes

AF:

0.0494

AC:

12260

AN:

247940

AF XY:

0.0455

show subpopulations

Gnomad AFR exome

AF:

0.183

Gnomad AMR exome

AF:

0.0398

Gnomad ASJ exome

AF:

0.00582

Gnomad EAS exome

AF:

0.150

Gnomad FIN exome

AF:

0.0780

Gnomad NFE exome

AF:

0.0170

Gnomad OTH exome

AF:

0.0467

GnomAD4 exome

AF:

0.0288

AC:

42133

AN:

1460678

Hom.:

1548

Cov.:

AF XY:

0.0286

AC XY:

20783

AN XY:

726590

show subpopulations

African (AFR)

AF:

0.177

AC:

5916

AN:

33418

American (AMR)

AF:

0.0424

AC:

1893

AN:

44660

Ashkenazi Jewish (ASJ)

AF:

0.00682

AC:

178

AN:

26118

East Asian (EAS)

AF:

0.148

AC:

5853

AN:

39648

South Asian (SAS)

AF:

0.0421

AC:

3630

AN:

86152

European-Finnish (FIN)

AF:

0.0736

AC:

3912

AN:

53152

Middle Eastern (MID)

AF:

0.0466

AC:

252

AN:

5406

European-Non Finnish (NFE)

AF:

0.0163

AC:

18087

AN:

1111824

Other (OTH)

AF:

0.0400

AC:

2412

AN:

60300

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

2362

4724

7086

9448

11810

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

888

1776

2664

3552

4440

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0740

AC:

11269

AN:

152202

Hom.:

784

Cov.:

AF XY:

0.0770

AC XY:

5726

AN XY:

74404

show subpopulations

African (AFR)

AF:

0.177

AC:

7340

AN:

41522

American (AMR)

AF:

0.0484

AC:

739

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00576

AC:

AN:

3470

East Asian (EAS)

AF:

0.148

AC:

762

AN:

5158

South Asian (SAS)

AF:

0.0453

AC:

218

AN:

4814

European-Finnish (FIN)

AF:

0.0819

AC:

869

AN:

10614

Middle Eastern (MID)

AF:

0.0272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0167

AC:

1139

AN:

68024

Other (OTH)

AF:

0.0691

AC:

146

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

503

1005

1508

2010

2513

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

118

236

354

472

590

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0362

Hom.:

1097

Bravo

AF:

0.0789

TwinsUK

AF:

0.0178

AC:

ALSPAC

AF:

0.0143

AC:

ESP6500AA

AF:

0.176

AC:

774

ESP6500EA

AF:

0.0156

AC:

134

ExAC

AF:

0.0502

AC:

6085

Asia WGS

AF:

0.0940

AC:

326

AN:

3478

EpiCase

AF:

0.0164

EpiControl

AF:

0.0157

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Uncertain

-0.030

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.82

Eigen

Uncertain

0.40

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.93

MetaRNN

Benign

0.0022

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.88

PhyloP100

5.6

PrimateAI

Benign

0.43

PROVEAN

Uncertain

-3.5

REVEL

Uncertain

0.63

Sift

Uncertain

0.015

Sift4G

Uncertain

0.028

Polyphen

0.98

Vest4

0.27

MPC

0.27

ClinPred

0.042

GERP RS

4.4

Varity_R

0.77

gMVP

0.80

Mutation Taster

=88/12

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over