NM_003602.5:c.547C>T

Variant names:

• chr7-73331735-C-T
• rs147213094
• NM_003602.5:c.547C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_003602.5(FKBP6):​c.547C>T​(p.Arg183Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00444 in 1,613,296 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0026 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0046 (24 hom.)
• Consequence: FKBP6 NM_003602.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.43
• Publications: 11 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: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.034024477).
• BP6: Variant 7-73331735-C-T is Benign according to our data. Variant chr7-73331735-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2657551.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

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.547C>T	p.Arg183Cys	missense	Exon 5 of 9	NP_003593.3
	FKBP6	NM_001135211.3		c.532C>T	p.Arg178Cys	missense	Exon 5 of 9	NP_001128683.1	O75344-2
	FKBP6	NM_001281304.2		c.457C>T	p.Arg153Cys	missense	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.547C>T	p.Arg183Cys	missense	Exon 5 of 9	ENSP00000252037.4	O75344-1
	FKBP6	ENST00000429879.5	TSL:1	n.547C>T		non_coding_transcript_exon	Exon 5 of 8	ENSP00000403908.1	F8WD36
	FKBP6	ENST00000431982.6	TSL:2	c.532C>T	p.Arg178Cys	missense	Exon 5 of 9	ENSP00000416277.2	O75344-2

Frequencies

GnomAD3 genomes AF: 0.00264 AC: 401 AN: 152080 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000869

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00482

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.00297 AC: 740 AN: 249554 AF XY: 0.00292

Gnomad AFR exome AF: 0.000839

Gnomad AMR exome AF: 0.000261

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00348

Gnomad NFE exome AF: 0.00555

Gnomad OTH exome AF: 0.00198

GnomAD4 exome AF: 0.00463 AC: 6763 AN: 1461098 Hom.: 24 Cov.: 31 AF XY: 0.00458 AC XY: 3329 AN XY: 726872

African (AFR) AF: 0.000747 AC: 25 AN: 33466

American (AMR) AF: 0.000246 AC: 11 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0000765 AC: 2 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39694

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86252

European-Finnish (FIN) AF: 0.00346 AC: 185 AN: 53416

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.00572 AC: 6355 AN: 1111270

Other (OTH) AF: 0.00291 AC: 176 AN: 60378

GnomAD4 genome AF: 0.00263 AC: 401 AN: 152198 Hom.: 2 Cov.: 32 AF XY: 0.00239 AC XY: 178 AN XY: 74418

African (AFR) AF: 0.000867 AC: 36 AN: 41530

American (AMR) AF: 0.000327 AC: 5 AN: 15296

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00283 AC: 30 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00483 AC: 328 AN: 67978

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.00452 Hom.: 9

Bravo AF: 0.00270

TwinsUK AF: 0.00620 AC: 23

ALSPAC AF: 0.00389 AC: 15

ESP6500AA AF: 0.000269 AC: 1

ESP6500EA AF: 0.00415 AC: 34

ExAC AF: 0.00315 AC: 381

EpiCase AF: 0.00469

EpiControl AF: 0.00421

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.071	T
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.57	D
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.081	D
MetaRNN	Benign	0.034	T
MetaSVM	Uncertain	0.019	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		2.4
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-3.4	D
REVEL	Pathogenic	0.67
Sift	Uncertain	0.019	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.81
MVP		0.88
MPC		0.99
ClinPred		0.026	T
GERP RS		5.5
Varity_R		0.14
gMVP		0.42
Mutation Taster		=78/22	polymorphism

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

Other links and lift over

dbSNP: rs147213094; hg19: chr7-72745738; COSMIC: COSV99048143; COSMIC: COSV99048143;