12-8660876-A-C

Variant names:

• chr12-8660876-A-C
• rs1555140533
• NM_003480.4:c.81T>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_003480.4(MFAP5):​c.81T>G​(p.Asn27Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000682 in 1,612,584 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict 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. N27N) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: MFAP5 NM_003480.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.129
• 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, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics
• familial thoracic aortic aneurysm and aortic dissection

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

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.11654356).
• BS2: High AC in GnomAdExome4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MFAP5	NM_003480.4	c.81T>G	p.Asn27Lys	missense_variant	Exon 3 of 10	ENST00000359478.7	NP_003471.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MFAP5	ENST00000359478.7	c.81T>G	p.Asn27Lys	missense_variant	Exon 3 of 10	1	NM_003480.4	ENSP00000352455.2

Frequencies

GnomAD3 genomes AF: 0.00000659 AC: 1 AN: 151796 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000685 AC: 10 AN: 1460788 Hom.: 0 Cov.: 30 AF XY: 0.00000826 AC XY: 6 AN XY: 726830

African (AFR) AF: 0.00 AC: 0 AN: 33448

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.000252 AC: 10 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86220

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111078

Other (OTH) AF: 0.00 AC: 0 AN: 60352

GnomAD4 genome AF: 0.00000659 AC: 1 AN: 151796 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74104

African (AFR) AF: 0.00 AC: 0 AN: 41314

American (AMR) AF: 0.00 AC: 0 AN: 15194

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10522

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67988

Other (OTH) AF: 0.00 AC: 0 AN: 2088

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Connective tissue disorder Uncertain:1

Nov 01, 2016

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	5.7
DANN	Benign	0.93
DEOGEN2	Uncertain	0.48	T;D;.;D;.;D
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.051	N
LIST_S2	Benign	0.64	T;T;.;T;T;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.12	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L;.;L;.;L;.
PhyloP100		-0.13
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.4	N;N;N;N;N;N
REVEL	Benign	0.044
Sift	Benign	0.031	D;D;D;D;D;D
Sift4G	Benign	0.20	T;T;T;D;T;T
Polyphen		0.56	P;P;.;.;.;.
Vest4		0.37
MutPred		0.61		Gain of ubiquitination at N27 (P = 0.0117);Gain of ubiquitination at N27 (P = 0.0117);Gain of ubiquitination at N27 (P = 0.0117);Gain of ubiquitination at N27 (P = 0.0117);Gain of ubiquitination at N27 (P = 0.0117);Gain of ubiquitination at N27 (P = 0.0117);
MVP		0.10
MPC		0.32
ClinPred		0.32	T
GERP RS		-3.6
Varity_R		0.091
gMVP		0.13
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs1555140533; hg19: chr12-8813472;