chr5-75374198-GAAAAAA-G

Variant names:

• chr5-75374198-GAAAAAA-G
• rs749454395
• ENST00000261415.12:c.*9+5133_*9+5138delTTTTTT

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_001130105.1(CERT1):​c.*10-13_*10-8delTTTTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000309 in 304,020 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: 𝑓 0.00013 (0 hom., cov: 29)
  • Exomes 𝑓: 0.00038 (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: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAd4 at 11 AD gene.

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.*10-13_*10-8delTTTTTT		splice_region intron	N/A	NP_001123577.1	Q9Y5P4-3
	CERT1	NM_001379002.1		c.*9+5133_*9+5138delTTTTTT		intron	N/A	NP_001365931.1	Q9Y5P4-1
	CERT1	NM_005713.3		c.*10-13_*10-8delTTTTTT		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+5133_*9+5138delTTTTTT		intron	N/A	ENSP00000261415.8	Q9Y5P4-1
	CERT1	ENST00000405807.10	TSL:5	c.*10-13_*10-8delTTTTTT		splice_region intron	N/A	ENSP00000383996.4	Q9Y5P4-3
	CERT1	ENST00000957920.1		c.*10-13_*10-8delTTTTTT		splice_region intron	N/A	ENSP00000627979.1

Frequencies

GnomAD3 genomes AF: 0.000130 AC: 11 AN: 84604 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.000408

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000138

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000378 AC: 83 AN: 219416 Hom.: 0 AF XY: 0.000483 AC XY: 54 AN XY: 111720

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

African (AFR) AF: 0.000471 AC: 3 AN: 6364

American (AMR) AF: 0.00 AC: 0 AN: 6662

Ashkenazi Jewish (ASJ) AF: 0.000726 AC: 6 AN: 8264

East Asian (EAS) AF: 0.000194 AC: 4 AN: 20626

South Asian (SAS) AF: 0.00 AC: 0 AN: 2470

European-Finnish (FIN) AF: 0.000291 AC: 5 AN: 17166

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1146

European-Non Finnish (NFE) AF: 0.000408 AC: 58 AN: 142204

Other (OTH) AF: 0.000482 AC: 7 AN: 14514

⚠️ 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: 0.000130 AC: 11 AN: 84604 Hom.: 0 Cov.: 29 AF XY: 0.000125 AC XY: 5 AN XY: 39978

African (AFR) AF: 0.000408 AC: 10 AN: 24482

American (AMR) AF: 0.000138 AC: 1 AN: 7248

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2136

East Asian (EAS) AF: 0.00 AC: 0 AN: 3096

South Asian (SAS) AF: 0.00 AC: 0 AN: 2658

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 136

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 39538

Other (OTH) AF: 0.00 AC: 0 AN: 1096

Alfa AF: 0.00 Hom.: 0

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;