rs78289603

chr2-46907878-C-Achr2-46907878-C-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The NM_139279.6(MCFD2):c.241G>T(p.Asp81Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D81H) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MCFD2 NM_139279.6 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.33

Genes affected

MCFD2 (HGNC:18451): (multiple coagulation factor deficiency 2, ER cargo receptor complex subunit) This gene encodes a soluble luminal protein with two calmodulin-like EF-hand motifs at its C-terminus. This protein forms a complex with LMAN1 (lectin mannose binding protein 1; also known as ERGIC-53) that facilitates the transport of coagulation factors V (FV) and VIII (FVIII) from the endoplasmic reticulum to the Golgi apparatus via an endoplasmic reticulum Golgi intermediate compartment (ERGIC). Mutations in this gene cause combined deficiency of FV and FVIII (F5F8D); a rare autosomal recessive bleeding disorder characterized by mild to moderate bleeding and coordinate reduction in plasma FV and FVIII levels. This protein has also been shown to maintain stem cell potential in adult central nervous system and is a marker for testicular germ cell tumors. The 3' UTR of this gene contains a transposon-like human repeat element named 'THE 1'. A processed RNA pseudogene of this gene is on chromosome 6p22.1. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Apr 2016]

(HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM1: In a chain Multiple coagulation factor deficiency protein 2 (size 119) in uniprot entity MCFD2_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_139279.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant 2-46907878-C-A is Pathogenic according to our data. Variant chr2-46907878-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 2872.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MCFD2	NM_139279.6	c.241G>T	p.Asp81Tyr	missense_variant	3/4	ENST00000319466.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MCFD2	ENST00000319466.9	c.241G>T	p.Asp81Tyr	missense_variant	3/4	1	NM_139279.6	P1
	ENST00000429761.1	n.1035C>A		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00209 Hom.: 0

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Factor 5 and Factor VIII, combined deficiency of, 2 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 15, 2008

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.59
Cadd	Pathogenic	32
Dann	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.97
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;.;.;.;.;D;.;.;D;.;D;D
M_CAP	Pathogenic	0.66	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-9.0	D;D;D;D;D;.;D;D;D;D;D;D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D;D;D;D;D;.;D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;.;D;D;D;D;D;D
Polyphen		1.0	.;D;.;D;.;.;D;D;.;D;D;.
Vest4		0.99
MutPred		0.93		.;Loss of phosphorylation at Y82 (P = 0.0831);.;Loss of phosphorylation at Y82 (P = 0.0831);.;Loss of phosphorylation at Y82 (P = 0.0831);Loss of phosphorylation at Y82 (P = 0.0831);Loss of phosphorylation at Y82 (P = 0.0831);.;Loss of phosphorylation at Y82 (P = 0.0831);Loss of phosphorylation at Y82 (P = 0.0831);.;
MVP		1.0
MPC		0.20
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.99
gMVP		0.95

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

Publications

LitVar

Other links and lift over

dbSNP: rs78289603; hg19: chr2-47135017;