chr5-75374198-GAA-G

Variant names:

• chr5-75374198-GAA-G
• rs749454395
• ENST00000261415.12:c.*9+5137_*9+5138delTT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_001130105.1(CERT1):​c.*10-9_*10-8delTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0567 in 286,150 control chromosomes in the GnomAD database, including 40 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.025 (40 hom., cov: 29)
  • Exomes 𝑓: 0.070 (0 hom.)
• Consequence: CERT1 NM_001130105.1 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.131
• Publications: 0 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 -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0794 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001130105.1. 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
	CERT1	NM_001130105.1		c.*10-9_*10-8delTT		splice_region intron	N/A	NP_001123577.1	Q9Y5P4-3
	CERT1	NM_001379002.1		c.*9+5137_*9+5138delTT		intron	N/A	NP_001365931.1	Q9Y5P4-1
	CERT1	NM_005713.3		c.*10-9_*10-8delTT		splice_region intron	N/A	NP_005704.1	Q9Y5P4-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CERT1	ENST00000261415.12	TSL:1	c.*9+5137_*9+5138delTT		intron	N/A	ENSP00000261415.8	Q9Y5P4-1
	CERT1	ENST00000405807.10	TSL:5	c.*10-9_*10-8delTT		splice_region intron	N/A	ENSP00000383996.4	Q9Y5P4-3
	CERT1	ENST00000957920.1		c.*10-9_*10-8delTT		splice_region intron	N/A	ENSP00000627979.1

Frequencies

GnomAD3 genomes AF: 0.0252 AC: 2133 AN: 84562 Hom.: 40 Cov.: 29

Gnomad AFR AF: 0.0824

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00924

Gnomad ASJ AF: 0.000468

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00715

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0147

Gnomad NFE AF: 0.000304

Gnomad OTH AF: 0.0155

GnomAD4 exome AF: 0.0699 AC: 14080 AN: 201568 Hom.: 0 AF XY: 0.0690 AC XY: 7076 AN XY: 102528

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.116 AC: 689 AN: 5936

American (AMR) AF: 0.0687 AC: 420 AN: 6110

Ashkenazi Jewish (ASJ) AF: 0.0674 AC: 513 AN: 7610

East Asian (EAS) AF: 0.0645 AC: 1224 AN: 18966

South Asian (SAS) AF: 0.0713 AC: 164 AN: 2300

European-Finnish (FIN) AF: 0.0675 AC: 1079 AN: 15996

Middle Eastern (MID) AF: 0.0698 AC: 75 AN: 1074

European-Non Finnish (NFE) AF: 0.0687 AC: 8952 AN: 130230

Other (OTH) AF: 0.0722 AC: 964 AN: 13346

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0253 AC: 2136 AN: 84582 Hom.: 40 Cov.: 29 AF XY: 0.0257 AC XY: 1026 AN XY: 39984

African (AFR) AF: 0.0824 AC: 2018 AN: 24498

American (AMR) AF: 0.00923 AC: 67 AN: 7256

Ashkenazi Jewish (ASJ) AF: 0.000468 AC: 1 AN: 2136

East Asian (EAS) AF: 0.00 AC: 0 AN: 3086

South Asian (SAS) AF: 0.00720 AC: 19 AN: 2640

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 3708

Middle Eastern (MID) AF: 0.0156 AC: 2 AN: 128

European-Non Finnish (NFE) AF: 0.000304 AC: 12 AN: 39520

Other (OTH) AF: 0.0154 AC: 17 AN: 1104

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.13
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: rs749454395; hg19: chr5-74670023;