chr5-75374198-G-GA

Variant names:

• chr5-75374198-G-GA
• rs749454395
• ENST00000261415.12:c.*9+5138_*9+5139insT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_001130105.1(CERT1):​c.*10-8dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0526 in 301,794 control chromosomes in the GnomAD database, including 3 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 0.0050 (3 hom., cov: 29)
  • Exomes 𝑓: 0.071 (0 hom.)
• Consequence: CERT1 NM_001130105.1 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.108
• 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.

• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00504 (426/84538) while in subpopulation EAS AF = 0.0269 (83/3082). AF 95% confidence interval is 0.0223. There are 3 homozygotes in GnomAd4. There are 221 alleles in the male GnomAd4 subpopulation. Median coverage is 29. This position passed quality control check.
• BS2: High AC in GnomAd4 at 426 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.*10-8dupT		splice_region intron	N/A	NP_001123577.1	Q9Y5P4-3
	CERT1	NM_001379002.1		c.*9+5138dupT		intron	N/A	NP_001365931.1	Q9Y5P4-1
	CERT1	NM_005713.3		c.*10-8dupT		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+5138_*9+5139insT		intron	N/A	ENSP00000261415.8	Q9Y5P4-1
	CERT1	ENST00000405807.10	TSL:5	c.*10-8_*10-7insT		splice_region intron	N/A	ENSP00000383996.4	Q9Y5P4-3
	CERT1	ENST00000957920.1		c.*10-8_*10-7insT		splice_region intron	N/A	ENSP00000627979.1

Frequencies

GnomAD3 genomes AF: 0.00505 AC: 427 AN: 84518 Hom.: 3 Cov.: 29

Gnomad AFR AF: 0.00601

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00497

Gnomad ASJ AF: 0.000468

Gnomad EAS AF: 0.0275

Gnomad SAS AF: 0.00715

Gnomad FIN AF: 0.00378

Gnomad MID AF: 0.00735

Gnomad NFE AF: 0.00301

Gnomad OTH AF: 0.00456

GnomAD4 exome AF: 0.0711 AC: 15454 AN: 217256 Hom.: 0 Cov.: 0 AF XY: 0.0721 AC XY: 7979 AN XY: 110628

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

African (AFR) AF: 0.0588 AC: 371 AN: 6310

American (AMR) AF: 0.0638 AC: 422 AN: 6610

Ashkenazi Jewish (ASJ) AF: 0.0703 AC: 576 AN: 8196

East Asian (EAS) AF: 0.0695 AC: 1419 AN: 20406

South Asian (SAS) AF: 0.0606 AC: 149 AN: 2458

European-Finnish (FIN) AF: 0.0811 AC: 1381 AN: 17038

Middle Eastern (MID) AF: 0.0732 AC: 83 AN: 1134

European-Non Finnish (NFE) AF: 0.0714 AC: 10041 AN: 140698

Other (OTH) AF: 0.0702 AC: 1012 AN: 14406

⚠️ 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: 0.00504 AC: 426 AN: 84538 Hom.: 3 Cov.: 29 AF XY: 0.00553 AC XY: 221 AN XY: 39970

African (AFR) AF: 0.00604 AC: 148 AN: 24506

American (AMR) AF: 0.00497 AC: 36 AN: 7248

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

East Asian (EAS) AF: 0.0269 AC: 83 AN: 3082

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

European-Finnish (FIN) AF: 0.00378 AC: 14 AN: 3708

Middle Eastern (MID) AF: 0.00781 AC: 1 AN: 128

European-Non Finnish (NFE) AF: 0.00301 AC: 119 AN: 39484

Other (OTH) AF: 0.00453 AC: 5 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		0.11
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;