chr7-30014872-CCTT-C

Variant names:

• chr7-30014872-CCTT-C
• rs542254849
• NM_017946.4:c.496_498delAAG

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 1P and 9B. PM4_Supporting BP6 BS1 BS2

The NM_017946.4(FKBP14):​c.496_498delAAG​(p.Lys166del) variant causes a conservative inframe deletion change. The variant allele was found at a frequency of 0.00136 in 1,594,244 control chromosomes in the GnomAD database, including 7 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00099 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (7 hom.)
• Consequence: FKBP14 NM_017946.4 conservative_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:5
• Conservation: PhyloP100: 5.79
• Publications: 1 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: Benign. The variant received -8 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_017946.4. Strenght limited to Supporting due to length of the change: 1aa.
• BP6: Variant 7-30014872-CCTT-C is Benign according to our data. Variant chr7-30014872-CCTT-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 432169.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000986 (150/152192) while in subpopulation SAS AF = 0.00228 (11/4816). AF 95% confidence interval is 0.00128. There are 0 homozygotes in GnomAd4. There are 72 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 7 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017946.4. 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
	FKBP14	NM_017946.4	MANE Select	c.496_498delAAG	p.Lys166del	conservative_inframe_deletion	Exon 4 of 4	NP_060416.1	Q9NWM8
	FKBP14	NR_046478.2		n.782_784delAAG		non_coding_transcript_exon	Exon 5 of 5
	FKBP14	NR_046479.2		n.538_540delAAG		non_coding_transcript_exon	Exon 3 of 3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FKBP14	ENST00000222803.10	TSL:1 MANE Select	c.496_498delAAG	p.Lys166del	conservative_inframe_deletion	Exon 4 of 4	ENSP00000222803.5	Q9NWM8
	FKBP14	ENST00000419018.1	TSL:1	n.*143_*145delAAG		non_coding_transcript_exon	Exon 3 of 3	ENSP00000406270.1	F8WBZ0
	FKBP14	ENST00000419018.1	TSL:1	n.*143_*145delAAG		3_prime_UTR	Exon 3 of 3	ENSP00000406270.1	F8WBZ0

Frequencies

GnomAD3 genomes AF: 0.000986 AC: 150 AN: 152074 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000387

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000328

Gnomad ASJ AF: 0.00374

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.00147

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.000998 AC: 229 AN: 229478 AF XY: 0.00116

Gnomad AFR exome AF: 0.000314

Gnomad AMR exome AF: 0.000491

Gnomad ASJ exome AF: 0.00255

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000143

Gnomad NFE exome AF: 0.00117

Gnomad OTH exome AF: 0.00161

GnomAD4 exome AF: 0.00140 AC: 2015 AN: 1442052 Hom.: 7 AF XY: 0.00143 AC XY: 1027 AN XY: 717198

African (AFR) AF: 0.000247 AC: 8 AN: 32422

American (AMR) AF: 0.000463 AC: 18 AN: 38868

Ashkenazi Jewish (ASJ) AF: 0.00214 AC: 54 AN: 25188

East Asian (EAS) AF: 0.00 AC: 0 AN: 39414

South Asian (SAS) AF: 0.00177 AC: 145 AN: 81736

European-Finnish (FIN) AF: 0.000360 AC: 19 AN: 52732

Middle Eastern (MID) AF: 0.00106 AC: 6 AN: 5670

European-Non Finnish (NFE) AF: 0.00153 AC: 1692 AN: 1106466

Other (OTH) AF: 0.00123 AC: 73 AN: 59556

GnomAD4 genome AF: 0.000986 AC: 150 AN: 152192 Hom.: 0 Cov.: 32 AF XY: 0.000968 AC XY: 72 AN XY: 74414

African (AFR) AF: 0.000385 AC: 16 AN: 41518

American (AMR) AF: 0.000327 AC: 5 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00374 AC: 13 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00228 AC: 11 AN: 4816

European-Finnish (FIN) AF: 0.000189 AC: 2 AN: 10594

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.00147 AC: 100 AN: 68000

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.00153 Hom.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
-	1	-	Cardiovascular phenotype (1)
-	-	1	Ehlers-Danlos syndrome (1)
-	-	1	Ehlers-Danlos syndrome, kyphoscoliotic type, 2 (1)
-	-	1	FKBP14-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.8
Mutation Taster		=48/52	disease causing

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: rs542254849; hg19: chr7-30054488; COSMIC: COSV106093285;