15-88905884-C-G

Position:

• chr15-88905884-C-G

Variant summary

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

The NM_005928.4(MFGE8):​c.558G>C​(p.Trp186Cys) 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. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: MFGE8 NM_005928.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.466

Genes affected

MFGE8 (HGNC:7036): (milk fat globule EGF and factor V/VIII domain containing) This gene encodes a preproprotein that is proteolytically processed to form multiple protein products. The major encoded protein product, lactadherin, is a membrane glycoprotein that promotes phagocytosis of apoptotic cells. This protein has also been implicated in wound healing, autoimmune disease, and cancer. Lactadherin can be further processed to form a smaller cleavage product, medin, which comprises the major protein component of aortic medial amyloid (AMA). Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2015]

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=0.3716734).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MFGE8	NM_005928.4	c.558G>C	p.Trp186Cys	missense_variant	5/8	ENST00000268150.13	NP_005919.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MFGE8	ENST00000268150.13	c.558G>C	p.Trp186Cys	missense_variant	5/8	1	NM_005928.4	ENSP00000268150	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 11, 2023

The c.558G>C (p.W186C) alteration is located in exon 5 (coding exon 5) of the MFGE8 gene. This alteration results from a G to C substitution at nucleotide position 558, causing the tryptophan (W) at amino acid position 186 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	18
DANN	Benign	0.89
DEOGEN2	Uncertain	0.43	.;T;T;.;T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.28
FATHMM_MKL	Benign	0.41	N
LIST_S2	Benign	0.74	T;.;T;T;T
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.37	T;T;T;T;T
MetaSVM	Uncertain	0.47	D
MutationAssessor	Benign	0.20	N;N;N;.;.
MutationTaster	Benign	0.94	D;D;D;D;D
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.96	N;N;N;N;N
REVEL	Uncertain	0.37
Sift	Benign	0.048	D;T;T;T;T
Sift4G	Benign	0.17	T;T;T;T;.
Polyphen		0.85	P;P;P;.;.
Vest4		0.24
MutPred		0.63		Loss of ubiquitination at K188 (P = 0.0537);Loss of ubiquitination at K188 (P = 0.0537);Loss of ubiquitination at K188 (P = 0.0537);.;Loss of ubiquitination at K188 (P = 0.0537);
MVP		0.96
MPC		0.23
ClinPred		0.22	T
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.13
gMVP		0.71

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: chr15-89449115; COSMIC: COSV51556142; COSMIC: COSV51556142;