chr5-75374198-GAAAA-G

Variant names:

• chr5-75374198-GAAAA-G
• rs749454395
• ENST00000261415.12:c.*9+5135_*9+5138delTTTT

Variant summary

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

The NM_001130105.1(CERT1):​c.*10-11_*10-8delTTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00652 in 296,762 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. 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 0.000012 (0 hom., cov: 29)
  • Exomes 𝑓: 0.0091 (0 hom.)
• Consequence: CERT1 NM_001130105.1 splice_region, 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: Uncertain_significance. The variant received 0 ACMG points.

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.*10-11_*10-8delTTTT		splice_region intron	N/A	NP_001123577.1	Q9Y5P4-3
	CERT1	NM_001379002.1		c.*9+5135_*9+5138delTTTT		intron	N/A	NP_001365931.1	Q9Y5P4-1
	CERT1	NM_005713.3		c.*10-11_*10-8delTTTT		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+5135_*9+5138delTTTT		intron	N/A	ENSP00000261415.8	Q9Y5P4-1
	CERT1	ENST00000405807.10	TSL:5	c.*10-11_*10-8delTTTT		splice_region intron	N/A	ENSP00000383996.4	Q9Y5P4-3
	CERT1	ENST00000957920.1		c.*10-11_*10-8delTTTT		splice_region intron	N/A	ENSP00000627979.1

Frequencies

GnomAD3 genomes AF: 0.0000118 AC: 1 AN: 84602 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000253

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00911 AC: 1933 AN: 212160 Hom.: 0 AF XY: 0.00887 AC XY: 957 AN XY: 107944

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

African (AFR) AF: 0.0101 AC: 62 AN: 6154

American (AMR) AF: 0.00968 AC: 62 AN: 6408

Ashkenazi Jewish (ASJ) AF: 0.00851 AC: 68 AN: 7992

East Asian (EAS) AF: 0.00858 AC: 172 AN: 20050

South Asian (SAS) AF: 0.0104 AC: 25 AN: 2410

European-Finnish (FIN) AF: 0.00958 AC: 159 AN: 16604

Middle Eastern (MID) AF: 0.0117 AC: 13 AN: 1114

European-Non Finnish (NFE) AF: 0.00888 AC: 1220 AN: 137364

Other (OTH) AF: 0.0108 AC: 152 AN: 14064

⚠️ 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: 0.0000118 AC: 1 AN: 84602 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 39976

African (AFR) AF: 0.00 AC: 0 AN: 24480

American (AMR) AF: 0.00 AC: 0 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: 0.0000253 AC: 1 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		0.13
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;