ENST00000261415.12:c.*9+5136_*9+5138delTTT

Variant names:

• chr5-75374198-GAAA-G
• rs749454395
• ENST00000261415.12:c.*9+5136_*9+5138delTTT

Variant summary

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

The ENST00000261415.12(CERT1):​c.*9+5136_*9+5138delTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.018 in 292,562 control chromosomes in the GnomAD database, including 1 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0019 (1 hom., cov: 29)
  • Exomes 𝑓: 0.025 (0 hom.)
• Consequence: CERT1 ENST00000261415.12 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.

• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00186 (157/84610) while in subpopulation EAS AF = 0.0438 (135/3084). AF 95% confidence interval is 0.0378. There are 1 homozygotes in GnomAd4. There are 84 alleles in the male GnomAd4 subpopulation. Median coverage is 29. This position passed quality control check.
• BS2: High AC in GnomAd4 at 157 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000261415.12. 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.*10-10_*10-8delTTT		splice_region intron	N/A	NP_001123577.1	Q9Y5P4-3
	CERT1	NM_001379002.1		c.*9+5136_*9+5138delTTT		intron	N/A	NP_001365931.1	Q9Y5P4-1
	CERT1	NM_005713.3		c.*10-10_*10-8delTTT		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+5136_*9+5138delTTT		intron	N/A	ENSP00000261415.8	Q9Y5P4-1
	CERT1	ENST00000405807.10	TSL:5	c.*10-10_*10-8delTTT		splice_region intron	N/A	ENSP00000383996.4	Q9Y5P4-3
	CERT1	ENST00000957920.1		c.*10-10_*10-8delTTT		splice_region intron	N/A	ENSP00000627979.1

Frequencies

GnomAD3 genomes AF: 0.00186 AC: 157 AN: 84590 Hom.: 1 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: 0.0436

Gnomad SAS AF: 0.00339

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000253

Gnomad OTH AF: 0.000912

GnomAD4 exome AF: 0.0246 AC: 5110 AN: 207952 Hom.: 0 AF XY: 0.0241 AC XY: 2542 AN XY: 105692

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

African (AFR) AF: 0.0266 AC: 161 AN: 6046

American (AMR) AF: 0.0234 AC: 147 AN: 6276

Ashkenazi Jewish (ASJ) AF: 0.0231 AC: 180 AN: 7796

East Asian (EAS) AF: 0.0350 AC: 686 AN: 19574

South Asian (SAS) AF: 0.0251 AC: 59 AN: 2350

European-Finnish (FIN) AF: 0.0204 AC: 336 AN: 16460

Middle Eastern (MID) AF: 0.0265 AC: 29 AN: 1096

European-Non Finnish (NFE) AF: 0.0233 AC: 3135 AN: 134622

Other (OTH) AF: 0.0275 AC: 377 AN: 13732

⚠️ 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: 0.00186 AC: 157 AN: 84610 Hom.: 1 Cov.: 29 AF XY: 0.00210 AC XY: 84 AN XY: 39996

African (AFR) AF: 0.000408 AC: 10 AN: 24524

American (AMR) AF: 0.000138 AC: 1 AN: 7254

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

East Asian (EAS) AF: 0.0438 AC: 135 AN: 3084

South Asian (SAS) AF: 0.00341 AC: 9 AN: 2640

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 128

European-Non Finnish (NFE) AF: 0.0000253 AC: 1 AN: 39526

Other (OTH) AF: 0.000906 AC: 1 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;