chr14-91891236-C-T

Variant names:

• chr14-91891236-C-T
• rs80338765
• NM_006329.4:c.604G>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BP6

The NM_006329.4(FBLN5):​c.604G>A​(p.Gly202Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000212 in 1,605,346 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G202V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00022 (1 hom.)
• Consequence: FBLN5 NM_006329.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:2 O:1
• Conservation: PhyloP100: 2.13
• Publications: 14 publications found

Genes affected

FBLN5 (HGNC:3602): (fibulin 5) The protein encoded by this gene is a secreted, extracellular matrix protein containing an Arg-Gly-Asp (RGD) motif and calcium-binding EGF-like domains. It promotes adhesion of endothelial cells through interaction of integrins and the RGD motif. It is prominently expressed in developing arteries but less so in adult vessels. However, its expression is reinduced in balloon-injured vessels and atherosclerotic lesions, notably in intimal vascular smooth muscle cells and endothelial cells. Therefore, the protein encoded by this gene may play a role in vascular development and remodeling. Defects in this gene are a cause of autosomal dominant cutis laxa, autosomal recessive cutis laxa type I (CL type I), and age-related macular degeneration type 3 (ARMD3). [provided by RefSeq, Jul 2008]

FBLN5 Gene-Disease associations (from GenCC):

• cutis laxa, autosomal dominant 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp
• cutis laxa, autosomal recessive, type 1A

  Inheritance: AR, SD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, Genomics England PanelApp
• Charcot-Marie-Tooth disease, demyelinating, IIA 1H

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• demyelinating hereditary motor and sensory neuropathy

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• macular degeneration, age-related, 3

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• autosomal dominant cutis laxa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary sensorimotor neuropathy with hyperelastic skin

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal recessive cutis laxa type 1

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.24265203).
• BP6: Variant 14-91891236-C-T is Benign according to our data. Variant chr14-91891236-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 21453.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006329.4. 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
	FBLN5	NM_006329.4	MANE Select	c.604G>A	p.Gly202Arg	missense	Exon 6 of 11	NP_006320.2
	FBLN5	NM_001384158.1		c.727G>A	p.Gly243Arg	missense	Exon 7 of 12	NP_001371087.1	G3XA98
	FBLN5	NM_001384159.1		c.655G>A	p.Gly219Arg	missense	Exon 6 of 11	NP_001371088.1	G3V4U0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBLN5	ENST00000342058.9	TSL:1 MANE Select	c.604G>A	p.Gly202Arg	missense	Exon 6 of 11	ENSP00000345008.4	Q9UBX5
	FBLN5	ENST00000267620.14	TSL:1	c.727G>A	p.Gly243Arg	missense	Exon 7 of 12	ENSP00000267620.10	G3XA98
	FBLN5	ENST00000556154.5	TSL:1	c.655G>A	p.Gly219Arg	missense	Exon 6 of 11	ENSP00000451982.2	G3V4U0

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 152158 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.000959

GnomAD2 exomes AF: 0.000278 AC: 70 AN: 251462 AF XY: 0.000250

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00107

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000220

Gnomad OTH exome AF: 0.000977

GnomAD4 exome AF: 0.000223 AC: 324 AN: 1453188 Hom.: 1 Cov.: 29 AF XY: 0.000209 AC XY: 151 AN XY: 723672

African (AFR) AF: 0.0000601 AC: 2 AN: 33302

American (AMR) AF: 0.00105 AC: 47 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0000767 AC: 2 AN: 26092

East Asian (EAS) AF: 0.00 AC: 0 AN: 39666

South Asian (SAS) AF: 0.00 AC: 0 AN: 86092

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.000348 AC: 2 AN: 5744

European-Non Finnish (NFE) AF: 0.000236 AC: 261 AN: 1104068

Other (OTH) AF: 0.000166 AC: 10 AN: 60084

GnomAD4 genome AF: 0.000105 AC: 16 AN: 152158 Hom.: 0 Cov.: 32 AF XY: 0.0000942 AC XY: 7 AN XY: 74326

African (AFR) AF: 0.0000241 AC: 1 AN: 41440

American (AMR) AF: 0.000196 AC: 3 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68026

Other (OTH) AF: 0.000959 AC: 2 AN: 2086

Alfa AF: 0.000199 Hom.: 0

Bravo AF: 0.000272

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000329 AC: 40

EpiCase AF: 0.000218

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	-	not provided (3)
-	-	1	Cutis laxa (1)
-	1	-	Cutis laxa, autosomal dominant (1)
-	-	1	Macular degeneration, age-related, 3 (1)
-	-	-	Cutis laxa, autosomal recessive, type 1A (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.62	D
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.43	D
MetaRNN	Benign	0.24	T
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		2.1
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-2.1	N
REVEL	Pathogenic	0.86
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.21	T
Polyphen		1.0	D
Vest4		0.52
MutPred		0.63		Gain of catalytic residue at R244 (P = 0.0179)
MVP		0.88
MPC		1.2
ClinPred		0.17	T
GERP RS		5.0
Varity_R		0.28
gMVP		0.92
Mutation Taster		=13/87	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs80338765; hg19: chr14-92357580;