chr7-73329440-C-A

Variant names:

• chr7-73329440-C-A
• rs375820982
• NM_003602.5:c.256C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_003602.5(FKBP6):​c.256C>A​(p.Leu86Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000101 in 1,589,920 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: FKBP6 NM_003602.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.69
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.256C>A	p.Leu86Ile	missense	Exon 3 of 9	NP_003593.3
	FKBP6	NM_001135211.3		c.241C>A	p.Leu81Ile	missense	Exon 3 of 9	NP_001128683.1	O75344-2
	FKBP6	NM_001362789.2		c.241C>A	p.Leu81Ile	missense	Exon 3 of 8	NP_001349718.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FKBP6	ENST00000252037.5	TSL:1 MANE Select	c.256C>A	p.Leu86Ile	missense	Exon 3 of 9	ENSP00000252037.4	O75344-1
	FKBP6	ENST00000429879.5	TSL:1	n.256C>A		non_coding_transcript_exon	Exon 3 of 8	ENSP00000403908.1	F8WD36
	FKBP6	ENST00000431982.6	TSL:2	c.241C>A	p.Leu81Ile	missense	Exon 3 of 9	ENSP00000416277.2	O75344-2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152158 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000239 AC: 6 AN: 251354 AF XY: 0.0000441

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.0000104 AC: 15 AN: 1437762 Hom.: 0 Cov.: 26 AF XY: 0.0000181 AC XY: 13 AN XY: 716920

African (AFR) AF: 0.00 AC: 0 AN: 32958

American (AMR) AF: 0.00 AC: 0 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25978

East Asian (EAS) AF: 0.00 AC: 0 AN: 39562

South Asian (SAS) AF: 0.0000816 AC: 7 AN: 85806

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5722

European-Non Finnish (NFE) AF: 0.00000459 AC: 5 AN: 1090088

Other (OTH) AF: 0.0000504 AC: 3 AN: 59538

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152158 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74324

African (AFR) AF: 0.00 AC: 0 AN: 41430

American (AMR) AF: 0.00 AC: 0 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68044

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000508 Hom.: 0

Bravo AF: 0.00000378

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000330 AC: 4

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.064	T
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.86	D
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.55	D
MetaSVM	Uncertain	0.19	D
MutationAssessor	Benign	1.9	M
PhyloP100		1.7
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.59
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.051	T
Polyphen		1.0	D
Vest4		0.51
MVP		0.92
MPC		1.0
ClinPred		0.65	D
GERP RS		4.8
Varity_R		0.77
gMVP		0.61
Mutation Taster		=60/40	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs375820982; hg19: chr7-72743443;