chr5-75374136-C-CT

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP6_Moderate BS2

The NM_001379004.1(CERT1):​c.1724dupA​(p.Leu576AlafsTer26) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00795 in 324,058 control chromosomes in the GnomAD database, including 3 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0034 (1 hom., cov: 31)
  • Exomes 𝑓: 0.011 (2 hom.)
• Consequence: CERT1 NM_001379004.1 frameshift
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• 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: Likely_benign. The variant received -6 ACMG points.

• BP6: Variant 5-75374136-C-CT is Benign according to our data. Variant chr5-75374136-C-CT is described in ClinVar as Likely_benign. ClinVar VariationId is 2673015.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 467 AD gene.

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.1724dupA	p.Leu576AlafsTer26	frameshift	Exon 16 of 16	NP_001365933.1	A0A2R8Y7C5
	CERT1	NM_001130105.1		c.*64dupA		3_prime_UTR	Exon 19 of 19	NP_001123577.1	Q9Y5P4-3
	CERT1	NM_005713.3		c.*64dupA		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+5200dupA		intron	N/A	ENSP00000261415.8	Q9Y5P4-1
	CERT1	ENST00000642556.1		c.1724dupA	p.Leu576AlafsTer26	frameshift	Exon 16 of 16	ENSP00000496016.1	A0A2R8Y7C5
	CERT1	ENST00000863487.1		c.*64dupA		splice_region	Exon 17 of 17	ENSP00000533546.1

Frequencies

GnomAD3 genomes AF: 0.00337 AC: 466 AN: 138444 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.000696

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000984

Gnomad ASJ AF: 0.00687

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000455

Gnomad FIN AF: 0.00865

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00513

Gnomad OTH AF: 0.00162

GnomAD4 exome AF: 0.0114 AC: 2108 AN: 185576 Hom.: 2 Cov.: 0 AF XY: 0.0113 AC XY: 1068 AN XY: 94444

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

African (AFR) AF: 0.00712 AC: 37 AN: 5200

American (AMR) AF: 0.00622 AC: 35 AN: 5626

Ashkenazi Jewish (ASJ) AF: 0.0106 AC: 72 AN: 6812

East Asian (EAS) AF: 0.00443 AC: 77 AN: 17398

South Asian (SAS) AF: 0.00681 AC: 17 AN: 2498

European-Finnish (FIN) AF: 0.0206 AC: 330 AN: 16038

Middle Eastern (MID) AF: 0.00411 AC: 4 AN: 974

European-Non Finnish (NFE) AF: 0.0120 AC: 1421 AN: 118758

Other (OTH) AF: 0.00937 AC: 115 AN: 12272

⚠️ 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: 0.00337 AC: 467 AN: 138482 Hom.: 1 Cov.: 31 AF XY: 0.00348 AC XY: 232 AN XY: 66638

African (AFR) AF: 0.000721 AC: 27 AN: 37440

American (AMR) AF: 0.000983 AC: 13 AN: 13228

Ashkenazi Jewish (ASJ) AF: 0.00687 AC: 23 AN: 3346

East Asian (EAS) AF: 0.00 AC: 0 AN: 4750

South Asian (SAS) AF: 0.000457 AC: 2 AN: 4376

European-Finnish (FIN) AF: 0.00865 AC: 68 AN: 7864

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

European-Non Finnish (NFE) AF: 0.00513 AC: 331 AN: 64512

Other (OTH) AF: 0.00161 AC: 3 AN: 1858

Alfa AF: 0.00283 Hom.: 0

Asia WGS AF: 0.00982 AC: 34 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

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

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;