12-8648164-C-G

Position:

• chr12-8648164-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The ENST00000359478.7(MFAP5):​c.449G>C​(p.Arg150Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,620 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MFAP5 ENST00000359478.7 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.16

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33130243).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MFAP5	NM_003480.4	c.449G>C	p.Arg150Thr	missense_variant	10/10	ENST00000359478.7	NP_003471.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MFAP5	ENST00000359478.7	c.449G>C	p.Arg150Thr	missense_variant	10/10	1	NM_003480.4	ENSP00000352455	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461620 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727122

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 07, 2021	This variant has not been reported in the literature in individuals affected with MFAP5-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with threonine at codon 150 of the MFAP5 protein (p.Arg150Thr). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and threonine. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.46	.;T;T;.;T;T;.
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.94	D;D;D;.;D;D;D
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.33	T;T;T;T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.97	.;L;.;.;.;.;.
MutationTaster	Benign	0.88	N;N;N;N;N;N
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-3.1	D;D;D;D;D;D;D
REVEL	Benign	0.17
Sift	Uncertain	0.010	D;D;D;D;D;D;D
Sift4G	Uncertain	0.0080	D;D;D;D;D;D;D
Polyphen		1.0	.;D;D;.;.;.;.
Vest4		0.58, 0.62, 0.59, 0.59, 0.68, 0.72
MutPred		0.31		.;Gain of phosphorylation at R150 (P = 0.0092);.;.;.;.;.;
MVP		0.15
MPC		0.93
ClinPred		0.94	D
GERP RS		3.9
Varity_R		0.19
gMVP		0.59

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-8800760;