5-75379360-G-A

Variant names:

• chr5-75379360-G-A
• NM_001379029.1:c.1861C>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001379029.1(CERT1):​c.1861C>T​(p.Pro621Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CERT1 NM_001379029.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.79

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.36465168).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CERT1	NM_001379029.1	c.1861C>T	p.Pro621Ser	missense_variant	Exon 17 of 17	ENST00000643780.2	NP_001365958.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CERT1	ENST00000643780.2	c.1861C>T	p.Pro621Ser	missense_variant	Exon 17 of 17		NM_001379029.1	ENSP00000495760.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Aug 24, 2020

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The alteration results in an amino acid change:_x000D_ _x000D_ The c.2245C>T (p.P749S) alteration is located in coding exon 18 of the CERT1 gene. This alteration results from a C to T substitution at nucleotide position 2245, causing the proline (P) at amino acid position 749 to be replaced by a serine (S). The alteration is not observed in population databases:_x000D_ _x000D_ Based on data from the Genome Aggregation Database (gnomAD), the COL4A3BP c.2245C>T alteration was not observed, with coverage at this position. The altered amino acid is conserved throughout evolution:_x000D_ _x000D_ The p.P749 amino acid is conserved in available vertebrate species; however, serine (S) is the reference amino acid in a few species. The alteration is predicted tolerated by in silico modeling:_x000D_ _x000D_ The p.P749S alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.043	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.66	.;.;D;.;.;.;.;D;D;.;.
Eigen	Uncertain	0.19
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.93	.;D;.;.;D;D;.;.;D;D;D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.36	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	.;.;L;.;.;.;.;L;L;.;.
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-5.5	.;.;.;.;.;.;.;D;.;.;.
REVEL	Benign	0.13
Sift	Uncertain	0.019	.;.;.;.;.;.;.;D;.;.;.
Sift4G	Uncertain	0.013	.;.;.;.;.;.;.;D;.;.;.
Polyphen		0.0040	B;B;B;.;.;.;B;B;B;.;B
Vest4		0.23
MutPred		0.49		.;.;Gain of MoRF binding (P = 0.038);.;.;.;.;Gain of MoRF binding (P = 0.038);Gain of MoRF binding (P = 0.038);.;.;
MVP		0.32
ClinPred		0.98	D
GERP RS		5.8
Varity_R		0.60
gMVP		0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-74675185;