7-73328448-A-C

Variant names:

• chr7-73328448-A-C
• NM_003602.5:c.20A>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_003602.5(FKBP6):​c.20A>C​(p.Asn7Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000285 in 1,401,626 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: FKBP6 NM_003602.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.52
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.063262165).

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.20A>C	p.Asn7Thr	missense	Exon 1 of 9	NP_003593.3
	FKBP6	NM_001281304.2		c.20A>C	p.Asn7Thr	missense	Exon 1 of 8	NP_001268233.1	O75344-3
	FKBP6	NM_001135211.3		c.43-127A>C		intron	N/A	NP_001128683.1	O75344-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FKBP6	ENST00000252037.5	TSL:1 MANE Select	c.20A>C	p.Asn7Thr	missense	Exon 1 of 9	ENSP00000252037.4	O75344-1
	FKBP6	ENST00000429879.5	TSL:1	n.20A>C		non_coding_transcript_exon	Exon 1 of 8	ENSP00000403908.1	F8WD36
	FKBP6	ENST00000413573.6	TSL:5	c.20A>C	p.Asn7Thr	missense	Exon 1 of 8	ENSP00000394952.2	O75344-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000285 AC: 4 AN: 1401626 Hom.: 0 Cov.: 29 AF XY: 0.00000433 AC XY: 3 AN XY: 692450

African (AFR) AF: 0.00 AC: 0 AN: 31980

American (AMR) AF: 0.00 AC: 0 AN: 35084

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24986

East Asian (EAS) AF: 0.00 AC: 0 AN: 36806

South Asian (SAS) AF: 0.00 AC: 0 AN: 79828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49720

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4266

European-Non Finnish (NFE) AF: 0.00000370 AC: 4 AN: 1080920

Other (OTH) AF: 0.00 AC: 0 AN: 58036

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

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	0.084
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	0.33
DANN	Benign	0.78
DEOGEN2	Benign	0.11	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.010	N
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.0095	T
MetaRNN	Benign	0.063	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L
PhyloP100		-1.5
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.83	N
REVEL	Benign	0.017
Sift	Benign	0.42	T
Sift4G	Benign	0.59	T
Polyphen		0.0	B
Vest4		0.15
MutPred		0.26		Gain of sheet (P = 0.0344)
MVP		0.32
MPC		2.0
ClinPred		0.043	T
GERP RS		-5.8
PromoterAI		0.0010	Neutral
Varity_R		0.042
gMVP		0.42
Mutation Taster		=99/1	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

hg19: chr7-72742451;