7-30014803-T-G

Variant names:

• chr7-30014803-T-G
• rs141843195
• NM_017946.4:c.568A>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_017946.4(FKBP14):​c.568A>C​(p.Lys190Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. K190K) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FKBP14 NM_017946.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.56
• Publications: 0 publications found

Genes affected

FKBP14 (HGNC:18625): (FKBP prolyl isomerase 14) The protein encoded by this gene is a member of the FK506-binding protein family of peptidyl-prolyl cis-trans isomerases. The encoded protein is found in the lumen of the endoplasmic reticulum, where it is thought to accelerate protein folding. Defects in this gene are a cause of a type of Ehlers-Danlos syndrome (EDS). Both a protein-coding variant and noncoding variants are transcribed from this gene. [provided by RefSeq, Mar 2012]

FKBP14-AS1 (HGNC:40990): (FKBP14 antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33162367).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FKBP14	NM_017946.4	c.568A>C	p.Lys190Gln	missense_variant	Exon 4 of 4	ENST00000222803.10	NP_060416.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FKBP14	ENST00000222803.10	c.568A>C	p.Lys190Gln	missense_variant	Exon 4 of 4	1	NM_017946.4	ENSP00000222803.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Ehlers-Danlos syndrome, kyphoscoliotic type, 2 Uncertain:1

Aug 27, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Uncertain	0.025	T
BayesDel_noAF	Benign	-0.20
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.23	T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.33	T
MetaSVM	Benign	-0.46	T
MutationAssessor	Benign	1.4	L
PhyloP100		7.6
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.23
Sift	Benign	0.12	T
Sift4G	Benign	0.15	T
Polyphen		0.96	D
Vest4		0.32
MutPred		0.33		Loss of ubiquitination at K190 (P = 0.0074);
MVP		0.84
MPC		0.42
ClinPred		0.90	D
GERP RS		5.9
Varity_R		0.50
gMVP		0.46
Mutation Taster		=48/52	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs141843195; hg19: chr7-30054419;