chr7-73331695-A-AGTGGCAGCTACGGAACGGGAGT

Variant names:

• chr7-73331695-A-AGTGGCAGCTACGGAACGGGAGT
• rs782102648
• NM_003602.5:c.508_529dupGTGGCAGCTACGGAACGGGAGT

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PP5_Moderate

The NM_003602.5(FKBP6):​c.508_529dupGTGGCAGCTACGGAACGGGAGT​(p.Phe177CysfsTer20) variant causes a frameshift change. The variant allele was found at a frequency of 0.00023 in 1,613,900 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00019 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00023 (0 hom.)
• Consequence: FKBP6 NM_003602.5 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 5.80
• Publications: 3 publications found

Genes affected

FKBP6 (HGNC:3722): (FKBP prolyl isomerase family member 6 (inactive)) The protein encoded by this gene is a cis-trans peptidyl-prolyl isomerase that may function in immunoregulation and basic cellular processes involving protein folding and trafficking. This gene is located in a chromosomal region that is deleted in Williams-Beuren syndrome. Defects in this gene may cause male infertility. There are multiple pseudogenes for this gene located nearby on chromosome 7. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

FKBP6 Gene-Disease associations (from GenCC):

• spermatogenic failure 77

  Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 7-73331695-A-AGTGGCAGCTACGGAACGGGAGT is Pathogenic according to our data. Variant chr7-73331695-A-AGTGGCAGCTACGGAACGGGAGT is described in ClinVar as Pathogenic. ClinVar VariationId is 1684033.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003602.5. 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
	FKBP6	NM_003602.5	MANE Select	c.508_529dupGTGGCAGCTACGGAACGGGAGT	p.Phe177CysfsTer20	frameshift	Exon 5 of 9	NP_003593.3
	FKBP6	NM_001135211.3		c.493_514dupGTGGCAGCTACGGAACGGGAGT	p.Phe172CysfsTer20	frameshift	Exon 5 of 9	NP_001128683.1	O75344-2
	FKBP6	NM_001281304.2		c.418_439dupGTGGCAGCTACGGAACGGGAGT	p.Phe147CysfsTer20	frameshift	Exon 4 of 8	NP_001268233.1	O75344-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FKBP6	ENST00000252037.5	TSL:1 MANE Select	c.508_529dupGTGGCAGCTACGGAACGGGAGT	p.Phe177CysfsTer20	frameshift	Exon 5 of 9	ENSP00000252037.4	O75344-1
	FKBP6	ENST00000429879.5	TSL:1	n.508_529dupGTGGCAGCTACGGAACGGGAGT		non_coding_transcript_exon	Exon 5 of 8	ENSP00000403908.1	F8WD36
	FKBP6	ENST00000431982.6	TSL:2	c.493_514dupGTGGCAGCTACGGAACGGGAGT	p.Phe172CysfsTer20	frameshift	Exon 5 of 9	ENSP00000416277.2	O75344-2

Frequencies

GnomAD3 genomes AF: 0.000191 AC: 29 AN: 152156 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000368

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000148 AC: 37 AN: 249588 AF XY: 0.000148

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.0000869

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000291

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000234 AC: 342 AN: 1461744 Hom.: 0 Cov.: 31 AF XY: 0.000232 AC XY: 169 AN XY: 727184

African (AFR) AF: 0.0000597 AC: 2 AN: 33478

American (AMR) AF: 0.0000447 AC: 2 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000296 AC: 329 AN: 1111888

Other (OTH) AF: 0.0000828 AC: 5 AN: 60390

GnomAD4 genome AF: 0.000191 AC: 29 AN: 152156 Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13 AN XY: 74336

African (AFR) AF: 0.0000965 AC: 4 AN: 41444

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000368 AC: 25 AN: 68010

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000432 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Male infertility (1)
1	-	-	Spermatogenic failure 77 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.8
Mutation Taster		=20/180	disease causing (fs/PTC)

Splicing

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

Other links and lift over

dbSNP: rs782102648; hg19: chr7-72745698;