rs201602377

Variant names:

• chr15-100402722-A-G
• rs201602377
• NM_001378789.1:c.1143T>C

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS1

The NM_001378789.1(CERS3):​c.1143T>C​(p.His381His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000342 in 1,614,088 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00023 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00035 (0 hom.)
• Consequence: CERS3 NM_001378789.1 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0370
• Publications: 0 publications found

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

Our verdict: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 15-100402722-A-G is Benign according to our data. Variant chr15-100402722-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 2645745.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.037 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00023 (35/152318) while in subpopulation SAS AF = 0.00311 (15/4824). AF 95% confidence interval is 0.00192. There are 0 homozygotes in GnomAd4. There are 24 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001378789.1. 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
	CERS3	NM_001378789.1	MANE Select	c.1143T>C	p.His381His	synonymous	Exon 12 of 12	NP_001365718.1	Q8IU89
	CERS3	NM_001290341.2		c.1176T>C	p.His392His	synonymous	Exon 14 of 14	NP_001277270.1	Q8IU89
	CERS3	NM_001290342.2		c.1143T>C	p.His381His	synonymous	Exon 13 of 13	NP_001277271.1	Q8IU89

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CERS3	ENST00000679737.1	MANE Select	c.1143T>C	p.His381His	synonymous	Exon 12 of 12	ENSP00000506641.1	Q8IU89
	CERS3	ENST00000284382.8	TSL:1	c.1143T>C	p.His381His	synonymous	Exon 13 of 13	ENSP00000284382.4	Q8IU89
	CERS3	ENST00000394113.5	TSL:1	c.1143T>C	p.His381His	synonymous	Exon 14 of 14	ENSP00000377672.3	Q8IU89

Frequencies

GnomAD3 genomes AF: 0.000230 AC: 35 AN: 152200 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00311

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000454 AC: 114 AN: 251272 AF XY: 0.000611

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000926

Gnomad NFE exome AF: 0.000238

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000354 AC: 517 AN: 1461770 Hom.: 0 Cov.: 30 AF XY: 0.000450 AC XY: 327 AN XY: 727208

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.0000894 AC: 4 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.000651 AC: 17 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00282 AC: 243 AN: 86252

European-Finnish (FIN) AF: 0.0000749 AC: 4 AN: 53392

Middle Eastern (MID) AF: 0.00191 AC: 11 AN: 5758

European-Non Finnish (NFE) AF: 0.000186 AC: 207 AN: 1111956

Other (OTH) AF: 0.000513 AC: 31 AN: 60386

GnomAD4 genome AF: 0.000230 AC: 35 AN: 152318 Hom.: 0 Cov.: 33 AF XY: 0.000322 AC XY: 24 AN XY: 74484

African (AFR) AF: 0.0000481 AC: 2 AN: 41576

American (AMR) AF: 0.0000653 AC: 1 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00311 AC: 15 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 68028

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.000197 Hom.: 0

Bravo AF: 0.000219

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000356

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.091
DANN	Benign	0.62
PhyloP100		0.037
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs201602377; hg19: chr15-100942927;