12-8648150-T-C

Variant names:

• chr12-8648150-T-C
• NM_003480.4:c.463A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003480.4(MFAP5):​c.463A>G​(p.Asn155Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N155S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MFAP5 NM_003480.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.886
• Publications: 0 publications found

Genes affected

MFAP5 (HGNC:29673): (microfibril associated protein 5) This gene encodes a 25-kD microfibril-associated glycoprotein which is a component of microfibrils of the extracellular matrix. The encoded protein promotes attachment of cells to microfibrils via alpha-V-beta-3 integrin. Deficiency of this gene in mice results in neutropenia. Alternate splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2014]

MFAP5 Gene-Disease associations (from GenCC):

• aortic aneurysm, familial thoracic 9

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: AD, Unknown Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23250416).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003480.4. 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
	MFAP5	NM_003480.4	MANE Select	c.463A>G	p.Asn155Asp	missense	Exon 10 of 10	NP_003471.1	Q13361-1
	MFAP5	NM_001297709.2		c.433A>G	p.Asn145Asp	missense	Exon 9 of 9	NP_001284638.1	Q13361-2
	MFAP5	NM_001297710.2		c.397A>G	p.Asn133Asp	missense	Exon 8 of 8	NP_001284639.1	F5GYX4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MFAP5	ENST00000359478.7	TSL:1 MANE Select	c.463A>G	p.Asn155Asp	missense	Exon 10 of 10	ENSP00000352455.2	Q13361-1
	MFAP5	ENST00000856658.1		c.520A>G	p.Asn174Asp	missense	Exon 10 of 10	ENSP00000526717.1
	MFAP5	ENST00000856657.1		c.463A>G	p.Asn155Asp	missense	Exon 11 of 11	ENSP00000526716.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T
Eigen	Benign	0.16
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.0051	T
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	L
PhyloP100		0.89
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-2.5	D
REVEL	Benign	0.12
Sift	Benign	0.087	T
Sift4G	Benign	0.37	T
Polyphen		0.95	P
Vest4		0.33
MutPred		0.14		Loss of MoRF binding (P = 0.0432)
MVP		0.12
MPC		0.34
ClinPred		0.57	D
GERP RS		4.8
Varity_R		0.24
gMVP		0.26
Mutation Taster		=86/14	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: chr12-8800746;