5-75374198-GAAAAAAA-G

Variant names:

• chr5-75374198-GAAAAAAA-G
• rs749454395
• ENST00000261415.12:c.*9+5132_*9+5138delTTTTTTT

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001130105.1(CERT1):​c.*10-14_*10-8delTTTTTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000182 in 219,804 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: CERT1 NM_001130105.1 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.975
• 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: Uncertain_significance. The variant received 2 ACMG points.

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

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.*10-14_*10-8delTTTTTTT		splice_region intron	N/A	NP_001123577.1	Q9Y5P4-3
	CERT1	NM_001379002.1		c.*9+5132_*9+5138delTTTTTTT		intron	N/A	NP_001365931.1	Q9Y5P4-1
	CERT1	NM_005713.3		c.*10-14_*10-8delTTTTTTT		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+5132_*9+5138delTTTTTTT		intron	N/A	ENSP00000261415.8	Q9Y5P4-1
	CERT1	ENST00000405807.10	TSL:5	c.*10-14_*10-8delTTTTTTT		splice_region intron	N/A	ENSP00000383996.4	Q9Y5P4-3
	CERT1	ENST00000957920.1		c.*10-14_*10-8delTTTTTTT		splice_region intron	N/A	ENSP00000627979.1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome AF: 0.0000182 AC: 4 AN: 219804 Hom.: 0 AF XY: 0.0000268 AC XY: 3 AN XY: 111942

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

African (AFR) AF: 0.00 AC: 0 AN: 6370

American (AMR) AF: 0.00 AC: 0 AN: 6668

Ashkenazi Jewish (ASJ) AF: 0.000121 AC: 1 AN: 8284

East Asian (EAS) AF: 0.00 AC: 0 AN: 20668

South Asian (SAS) AF: 0.00 AC: 0 AN: 2482

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 17206

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1152

European-Non Finnish (NFE) AF: 0.0000211 AC: 3 AN: 142426

Other (OTH) AF: 0.00 AC: 0 AN: 14548

⚠️ 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 Cov.: 29

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.97

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs749454395; hg19: chr5-74670023;