5-75374198-GAAAAAAAA-GAAAAAAA

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_001130105.1(CERT1):​c.*10-8delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.165 in 293,662 control chromosomes in the GnomAD database, including 75 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.039 (74 hom., cov: 29)
  • Exomes 𝑓: 0.22 (1 hom.)
• Consequence: CERT1 NM_001130105.1 splice_region, intron
• Clinical Significance: Likely benign criteria provided, single submitter B:3
• 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 -10 ACMG points.

• BP6: Variant 5-75374198-GA-G is Benign according to our data. Variant chr5-75374198-GA-G is described in ClinVar as Likely_benign. ClinVar VariationId is 1206283.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0988 is higher than 0.05.

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

Frequencies

GnomAD3 genomes AF: 0.0390 AC: 3296 AN: 84592 Hom.: 73 Cov.: 29

Gnomad AFR AF: 0.102

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0171

Gnomad ASJ AF: 0.0258

Gnomad EAS AF: 0.0820

Gnomad SAS AF: 0.0553

Gnomad FIN AF: 0.000539

Gnomad MID AF: 0.0515

Gnomad NFE AF: 0.00430

Gnomad OTH AF: 0.0310

GnomAD4 exome AF: 0.215 AC: 45013 AN: 209050 Hom.: 1 Cov.: 0 AF XY: 0.214 AC XY: 22739 AN XY: 106362

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

African (AFR) AF: 0.225 AC: 1371 AN: 6084

American (AMR) AF: 0.218 AC: 1391 AN: 6380

Ashkenazi Jewish (ASJ) AF: 0.219 AC: 1721 AN: 7862

East Asian (EAS) AF: 0.229 AC: 4498 AN: 19658

South Asian (SAS) AF: 0.212 AC: 507 AN: 2390

European-Finnish (FIN) AF: 0.217 AC: 3576 AN: 16484

Middle Eastern (MID) AF: 0.221 AC: 244 AN: 1106

European-Non Finnish (NFE) AF: 0.212 AC: 28715 AN: 135226

Other (OTH) AF: 0.216 AC: 2990 AN: 13860

⚠️ 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: 0.0390 AC: 3296 AN: 84612 Hom.: 74 Cov.: 29 AF XY: 0.0405 AC XY: 1622 AN XY: 40008

African (AFR) AF: 0.102 AC: 2504 AN: 24522

American (AMR) AF: 0.0171 AC: 124 AN: 7256

Ashkenazi Jewish (ASJ) AF: 0.0258 AC: 55 AN: 2132

East Asian (EAS) AF: 0.0826 AC: 255 AN: 3086

South Asian (SAS) AF: 0.0549 AC: 145 AN: 2640

European-Finnish (FIN) AF: 0.000539 AC: 2 AN: 3708

Middle Eastern (MID) AF: 0.0469 AC: 6 AN: 128

European-Non Finnish (NFE) AF: 0.00430 AC: 170 AN: 39530

Other (OTH) AF: 0.0317 AC: 35 AN: 1104

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	not provided (1)

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;