rs5744539

Variant names:

• chr5-75511291-C-T
• rs5744539
• NM_001379029.1:c.-84G>A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001130105.1(CERT1):​c.301G>A​(p.Asp101Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00163 in 1,566,594 control chromosomes in the GnomAD database, including 57 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0028 (9 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (48 hom.)
• Consequence: CERT1 NM_001130105.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.04

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]

POLK (HGNC:9183): (DNA polymerase kappa) This gene encodes a member of the DNA polymerase type-Y family of proteins. The encoded protein is a specialized DNA polymerase that catalyzes translesion DNA synthesis, which allows DNA replication in the presence of DNA lesions. Human cell lines lacking a functional copy of this gene exhibit impaired genome integrity and enhanced susceptibility to oxidative damage. Mutations in this gene that impair enzyme activity may be associated with prostate cancer in human patients. [provided by RefSeq, Sep 2016]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0024900734).
• BP6: Variant 5-75511291-C-T is Benign according to our data. Variant chr5-75511291-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 446020.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-75511291-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0028 (426/152252) while in subpopulation AMR AF= 0.0217 (332/15300). AF 95% confidence interval is 0.0198. There are 9 homozygotes in gnomad4. There are 211 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 426 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CERT1	NM_001379029.1	c.-84G>A		5_prime_UTR_variant	Exon 1 of 17	ENST00000643780.2	NP_001365958.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CERT1	ENST00000643780.2	c.-84G>A		5_prime_UTR_variant	Exon 1 of 17		NM_001379029.1	ENSP00000495760.1

Frequencies

GnomAD3 genomes AF: 0.00277 AC: 422 AN: 152134 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0215

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0110

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00573

GnomAD3 exomes AF: 0.00960 AC: 1603 AN: 166936 Hom.: 34 AF XY: 0.00713 AC XY: 647 AN XY: 90708

Gnomad AFR exome AF: 0.000488

Gnomad AMR exome AF: 0.0538

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0147

Gnomad SAS exome AF: 0.0000816

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000603

Gnomad OTH exome AF: 0.00738

GnomAD4 exome AF: 0.00150 AC: 2123 AN: 1414342 Hom.: 48 Cov.: 32 AF XY: 0.00126 AC XY: 880 AN XY: 699556

Gnomad4 AFR exome AF: 0.000124

Gnomad4 AMR exome AF: 0.0479

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00609

Gnomad4 SAS exome AF: 0.0000368

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000294

Gnomad4 OTH exome AF: 0.00150

GnomAD4 genome AF: 0.00280 AC: 426 AN: 152252 Hom.: 9 Cov.: 32 AF XY: 0.00283 AC XY: 211 AN XY: 74444

Gnomad4 AFR AF: 0.000505

Gnomad4 AMR AF: 0.0217

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0110

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00567

Alfa AF: 0.000919 Hom.: 0

Bravo AF: 0.00618

ExAC AF: 0.00471 AC: 537

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 24, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	19
DANN	Uncertain	1.0
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.026
FATHMM_MKL	Benign	0.41	N
LIST_S2	Benign	0.56	T
MetaRNN	Benign	0.0025	T
MetaSVM	Benign	-1.1	T
PrimateAI	Uncertain	0.76	T
Polyphen		0.19	B
ClinPred		0.024	T
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.37

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

Publications

LitVar

Other links and lift over

dbSNP: rs5744539; hg19: chr5-74807116;