5-75374136-CTTTT-CTTT

Variant names:

• chr5-75374136-CT-C
• rs545323650
• ENST00000261415.12:c.*9+5200delA

Variant summary

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

The NM_001379004.1(CERT1):​c.1724delA​(p.Lys575SerfsTer2) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000928 in 344,644 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00010 (0 hom.)
• Consequence: CERT1 NM_001379004.1 frameshift
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.786
• 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 0 ACMG points.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001379004.1. 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_001379004.1		c.1724delA	p.Lys575SerfsTer2	frameshift	Exon 16 of 16	NP_001365933.1	A0A2R8Y7C5
	CERT1	NM_001130105.1		c.*64delA		3_prime_UTR	Exon 19 of 19	NP_001123577.1	Q9Y5P4-3
	CERT1	NM_005713.3		c.*64delA		3_prime_UTR	Exon 18 of 18	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+5200delA		intron	N/A	ENSP00000261415.8	Q9Y5P4-1
	CERT1	ENST00000642556.1		c.1724delA	p.Lys575SerfsTer2	frameshift	Exon 16 of 16	ENSP00000496016.1	A0A2R8Y7C5
	CERT1	ENST00000863487.1		c.*64delA		splice_region	Exon 17 of 17	ENSP00000533546.1

Frequencies

GnomAD3 genomes AF: 0.0000867 AC: 12 AN: 138474 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000161

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000757

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000210

Gnomad SAS AF: 0.000227

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000465

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000102 AC: 21 AN: 206132 Hom.: 0 Cov.: 0 AF XY: 0.0000954 AC XY: 10 AN XY: 104798

⚠️ 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: 5862

American (AMR) AF: 0.000160 AC: 1 AN: 6246

Ashkenazi Jewish (ASJ) AF: 0.000131 AC: 1 AN: 7628

East Asian (EAS) AF: 0.00 AC: 0 AN: 19202

South Asian (SAS) AF: 0.000362 AC: 1 AN: 2762

European-Finnish (FIN) AF: 0.000114 AC: 2 AN: 17562

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1088

European-Non Finnish (NFE) AF: 0.000106 AC: 14 AN: 132206

Other (OTH) AF: 0.000147 AC: 2 AN: 13576

⚠️ 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: 0.0000794 AC: 11 AN: 138512 Hom.: 0 Cov.: 31 AF XY: 0.000120 AC XY: 8 AN XY: 66654

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

African (AFR) AF: 0.000160 AC: 6 AN: 37440

American (AMR) AF: 0.0000756 AC: 1 AN: 13230

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3348

East Asian (EAS) AF: 0.000211 AC: 1 AN: 4750

South Asian (SAS) AF: 0.000228 AC: 1 AN: 4378

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7866

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 254

European-Non Finnish (NFE) AF: 0.0000310 AC: 2 AN: 64534

Other (OTH) AF: 0.00 AC: 0 AN: 1858

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000490565), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.79
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: rs545323650; hg19: chr5-74669961;