rs698912

Variant names:

• chr5-75385948-T-C
• rs698912
• NM_001379029.1:c.1371A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001379029.1(CERT1):​c.1371A>G​(p.Glu457Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.228 in 1,586,116 control chromosomes in the GnomAD database, including 43,931 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4357 hom., cov: 32)
  • Exomes 𝑓: 0.23 (39574 hom.)
• Consequence: CERT1 NM_001379029.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.497
• Publications: 23 publications found

Genes affected

CERT1 (HGNC:2205): (ceramide transporter 1) This gene encodes a kinase that specifically phosphorylates the N-terminal region of the non-collagenous domain of the alpha 3 chain of type IV collagen, known as the Goodpasture antigen. Goodpasture disease is the result of an autoimmune response directed at this antigen. One isoform of this protein is also involved in ceramide intracellular transport. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

CERT1 Gene-Disease associations (from GenCC):

• intellectual disability, autosomal dominant 34

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 5-75385948-T-C is Benign according to our data. Variant chr5-75385948-T-C is described in ClinVar as Benign. ClinVar VariationId is 1275144.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.497 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.416 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CERT1	NM_001379029.1	c.1371A>G	p.Glu457Glu	synonymous_variant	Exon 13 of 17	ENST00000643780.2	NP_001365958.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CERT1	ENST00000643780.2	c.1371A>G	p.Glu457Glu	synonymous_variant	Exon 13 of 17		NM_001379029.1	ENSP00000495760.1

Frequencies

GnomAD3 genomes AF: 0.235 AC: 35691 AN: 152068 Hom.: 4351 Cov.: 32

Gnomad AFR AF: 0.258

Gnomad AMI AF: 0.281

Gnomad AMR AF: 0.182

Gnomad ASJ AF: 0.280

Gnomad EAS AF: 0.323

Gnomad SAS AF: 0.430

Gnomad FIN AF: 0.237

Gnomad MID AF: 0.212

Gnomad NFE AF: 0.209

Gnomad OTH AF: 0.227

GnomAD2 exomes AF: 0.240 AC: 56716 AN: 236308 AF XY: 0.250

Gnomad AFR exome AF: 0.253

Gnomad AMR exome AF: 0.139

Gnomad ASJ exome AF: 0.277

Gnomad EAS exome AF: 0.317

Gnomad FIN exome AF: 0.236

Gnomad NFE exome AF: 0.209

Gnomad OTH exome AF: 0.229

GnomAD4 exome AF: 0.227 AC: 325513 AN: 1433930 Hom.: 39574 Cov.: 31 AF XY: 0.233 AC XY: 165722 AN XY: 712372

African (AFR) AF: 0.263 AC: 8563 AN: 32534

American (AMR) AF: 0.146 AC: 6119 AN: 41946

Ashkenazi Jewish (ASJ) AF: 0.279 AC: 7082 AN: 25424

East Asian (EAS) AF: 0.337 AC: 13010 AN: 38552

South Asian (SAS) AF: 0.416 AC: 33290 AN: 80054

European-Finnish (FIN) AF: 0.235 AC: 12310 AN: 52416

Middle Eastern (MID) AF: 0.283 AC: 1606 AN: 5678

European-Non Finnish (NFE) AF: 0.209 AC: 229874 AN: 1098266

Other (OTH) AF: 0.231 AC: 13659 AN: 59060

GnomAD4 genome AF: 0.235 AC: 35724 AN: 152186 Hom.: 4357 Cov.: 32 AF XY: 0.240 AC XY: 17858 AN XY: 74394

African (AFR) AF: 0.258 AC: 10705 AN: 41516

American (AMR) AF: 0.182 AC: 2786 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.280 AC: 970 AN: 3468

East Asian (EAS) AF: 0.324 AC: 1678 AN: 5186

South Asian (SAS) AF: 0.431 AC: 2079 AN: 4822

European-Finnish (FIN) AF: 0.237 AC: 2509 AN: 10584

Middle Eastern (MID) AF: 0.207 AC: 61 AN: 294

European-Non Finnish (NFE) AF: 0.209 AC: 14207 AN: 68000

Other (OTH) AF: 0.224 AC: 473 AN: 2110

Alfa AF: 0.220 Hom.: 10436

Bravo AF: 0.227

Asia WGS AF: 0.356 AC: 1237 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jan 08, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

CERT1-related disorder Benign:1

Oct 21, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	6.6
DANN	Benign	0.64
PhyloP100		0.50
PromoterAI		0.0056	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=97/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs698912; hg19: chr5-74681773; COSMIC: COSV54656722; COSMIC: COSV54656722;