rs6041749

Variant names:

• chr20-1370028-T-C
• rs6041749
• NM_000801.5:c.*81A>G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000801.5(FKBP1A):​c.*81A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.431 in 1,548,388 control chromosomes in the GnomAD database, including 148,783 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.44 (15307 hom., cov: 33)
  • Exomes 𝑓: 0.43 (133476 hom.)
• Consequence: FKBP1A NM_000801.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0490

Genes affected

FKBP1A (HGNC:3711): (FKBP prolyl isomerase 1A) The protein encoded by this gene is a member of the immunophilin protein family, which play a role in immunoregulation and basic cellular processes involving protein folding and trafficking. The protein is a cis-trans prolyl isomerase that binds the immunosuppressants FK506 and rapamycin. It interacts with several intracellular signal transduction proteins including type I TGF-beta receptor. It also interacts with multiple intracellular calcium release channels, and coordinates multi-protein complex formation of the tetrameric skeletal muscle ryanodine receptor. In mouse, deletion of this homologous gene causes congenital heart disorder known as noncompaction of left ventricular myocardium. Multiple alternatively spliced variants, encoding the same protein, have been identified. The human genome contains five pseudogenes related to this gene, at least one of which is transcribed. [provided by RefSeq, Sep 2008]

SDCBP2-AS1 (HGNC:44314): (SDCBP2 antisense RNA 1)

ENSG00000274322 (HGNC:):

FKBP1A-SDCBP2 (HGNC:41997): (FKBP1A-SDCBP2 readthrough (NMD candidate)) This locus represents naturally occurring read-through transcription between the neighboring FK506 binding protein 1A, 12kDa and syndecan binding protein (syntenin) 2 genes on chromosome 20. The read-through transcript is a candidate for nonsense-mediated mRNA decay (NMD), and is unlikely to produce a protein product. [provided by RefSeq, Dec 2010]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 20-1370028-T-C is Benign according to our data. Variant chr20-1370028-T-C is described in ClinVar as [Benign]. Clinvar id is 1233437.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.492 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FKBP1A	NM_000801.5	c.*81A>G		3_prime_UTR_variant	Exon 5 of 5	ENST00000400137.9	NP_000792.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FKBP1A	ENST00000400137	c.*81A>G		3_prime_UTR_variant	Exon 5 of 5	1	NM_000801.5	ENSP00000383003.4
ENSG00000274322	ENST00000617804.1	n.204+21575A>G		intron_variant	Intron 3 of 5	4		ENSP00000479180.1

Frequencies

GnomAD3 genomes AF: 0.440 AC: 66832 AN: 152024 Hom.: 15311 Cov.: 33

Gnomad AFR AF: 0.498

Gnomad AMI AF: 0.664

Gnomad AMR AF: 0.391

Gnomad ASJ AF: 0.505

Gnomad EAS AF: 0.117

Gnomad SAS AF: 0.379

Gnomad FIN AF: 0.314

Gnomad MID AF: 0.620

Gnomad NFE AF: 0.455

Gnomad OTH AF: 0.482

GnomAD3 exomes AF: 0.386 AC: 56970 AN: 147768 Hom.: 12055 AF XY: 0.393 AC XY: 31232 AN XY: 79512

Gnomad AFR exome AF: 0.505

Gnomad AMR exome AF: 0.282

Gnomad ASJ exome AF: 0.509

Gnomad EAS exome AF: 0.124

Gnomad SAS exome AF: 0.395

Gnomad FIN exome AF: 0.310

Gnomad NFE exome AF: 0.460

Gnomad OTH exome AF: 0.448

GnomAD4 exome AF: 0.431 AC: 601241 AN: 1396246 Hom.: 133476 Cov.: 37 AF XY: 0.431 AC XY: 296836 AN XY: 688706

Gnomad4 AFR exome AF: 0.491

Gnomad4 AMR exome AF: 0.306

Gnomad4 ASJ exome AF: 0.508

Gnomad4 EAS exome AF: 0.119

Gnomad4 SAS exome AF: 0.395

Gnomad4 FIN exome AF: 0.323

Gnomad4 NFE exome AF: 0.447

Gnomad4 OTH exome AF: 0.441

GnomAD4 genome AF: 0.439 AC: 66848 AN: 152142 Hom.: 15307 Cov.: 33 AF XY: 0.428 AC XY: 31857 AN XY: 74352

Gnomad4 AFR AF: 0.498

Gnomad4 AMR AF: 0.391

Gnomad4 ASJ AF: 0.505

Gnomad4 EAS AF: 0.118

Gnomad4 SAS AF: 0.380

Gnomad4 FIN AF: 0.314

Gnomad4 NFE AF: 0.455

Gnomad4 OTH AF: 0.479

Alfa AF: 0.457 Hom.: 2975

Bravo AF: 0.447

Asia WGS AF: 0.255 AC: 891 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Aug 22, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 30215102) -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	11
DANN	Benign	0.79
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs6041749; hg19: chr20-1350672; COSMIC: COSV67750787; COSMIC: COSV67750787;