9-113169510-T-A

Variant names:

• chr9-113169510-T-A
• rs543834605
• NM_015258.2:c.3199A>T

Variant summary

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

The NM_015258.2(FKBP15):​c.3199A>T​(p.Met1067Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,706 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M1067V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FKBP15 NM_015258.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.92
• Publications: 0 publications found

Genes affected

FKBP15 (HGNC:23397): (FKBP prolyl isomerase family member 15) Predicted to enable actin binding activity and peptidyl-prolyl cis-trans isomerase activity. Predicted to be involved in endocytosis and protein peptidyl-prolyl isomerization. Located in membrane. [provided by Alliance of Genome Resources, Apr 2022]

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=0.037730694).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015258.2. 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
	FKBP15	NM_015258.2	MANE Select	c.3199A>T	p.Met1067Leu	missense	Exon 26 of 28	NP_056073.1	Q5T1M5-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FKBP15	ENST00000238256.8	TSL:1 MANE Select	c.3199A>T	p.Met1067Leu	missense	Exon 26 of 28	ENSP00000238256.3	Q5T1M5-1
	FKBP15	ENST00000446284.6	TSL:1	c.3199A>T	p.Met1067Leu	missense	Exon 26 of 28	ENSP00000416158.2	Q5T1M5-1
	FKBP15	ENST00000693271.1		c.3181A>T	p.Met1061Leu	missense	Exon 27 of 28	ENSP00000508580.1	A0A8I5KX71

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461706 Hom.: 0 Cov.: 36 AF XY: 0.00000138 AC XY: 1 AN XY: 727134

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

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

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111864

Other (OTH) AF: 0.00 AC: 0 AN: 60374

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.0010
DANN	Benign	0.26
DEOGEN2	Benign	0.0011	T
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.029	N
LIST_S2	Benign	0.37	T
M_CAP	Benign	0.0081	T
MetaRNN	Benign	0.038	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-0.065	N
PhyloP100		-2.9
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.44	N
REVEL	Benign	0.013
Sift	Benign	1.0	T
Sift4G	Benign	0.32	T
Polyphen		0.0	B
Vest4		0.11
MutPred		0.18		Loss of loop (P = 0.0603)
MVP		0.048
MPC		0.14
ClinPred		0.015	T
GERP RS		-7.8
Varity_R		0.038
Mutation Taster		=98/2	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: rs543834605; hg19: chr9-115931790;