NM_003480.4:c.472C>T

Variant names:

• chr12-8648141-G-A
• rs727502791
• NM_003480.4:c.472C>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 7P and 4B. PVS1_Moderate PS3 PP5 BS2

The NM_003480.4(MFAP5):​c.472C>T​(p.Arg158*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000205 in 1,461,746 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV002058191: Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID:25434006, PS3_S)." and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. R158R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: MFAP5 NM_003480.4 stop_gained
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6 U:1
• Conservation: PhyloP100: 2.10
• Publications: 6 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 3 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0958 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV002058191: Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID:25434006, PS3_S).; SCV003440434: Experimental studies have shown that this premature translational stop signal affects MFAP5 function (PMID: 25434006).
• PP5: Variant 12-8648141-G-A is Pathogenic according to our data. Variant chr12-8648141-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 162199.
• BS2: High AC in GnomAdExome4 at 30 AD,Unknown gene.

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.472C>T	p.Arg158*	stop_gained	Exon 10 of 10	NP_003471.1	Q13361-1
	MFAP5	NM_001297709.2		c.442C>T	p.Arg148*	stop_gained	Exon 9 of 9	NP_001284638.1	Q13361-2
	MFAP5	NM_001297710.2		c.406C>T	p.Arg136*	stop_gained	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.472C>T	p.Arg158*	stop_gained	Exon 10 of 10	ENSP00000352455.2	Q13361-1
	MFAP5	ENST00000856658.1		c.529C>T	p.Arg177*	stop_gained	Exon 10 of 10	ENSP00000526717.1
	MFAP5	ENST00000856657.1		c.472C>T	p.Arg158*	stop_gained	Exon 11 of 11	ENSP00000526716.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000438 AC: 11 AN: 251418 AF XY: 0.0000515

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000326

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000205 AC: 30 AN: 1461746 Hom.: 0 Cov.: 30 AF XY: 0.0000220 AC XY: 16 AN XY: 727176

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.000302 AC: 12 AN: 39692

South Asian (SAS) AF: 0.0000928 AC: 8 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

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

European-Non Finnish (NFE) AF: 0.00000899 AC: 10 AN: 1111916

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000595 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000412 AC: 5

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
4	1	-	Aortic aneurysm, familial thoracic 9 (5)
1	-	-	Isolated thoracic aortic aneurysm (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	36
DANN	Uncertain	1.0
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.82	D
PhyloP100		2.1
Vest4		0.23
GERP RS		3.9
Mutation Taster		=1/199	disease causing (ClinVar)

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: rs727502791; hg19: chr12-8800737;