rs1051317

Variant names:

• chr2-46903009-G-T
• rs1051317
• NM_139279.6:c.*2454C>A

Your query was ambiguous. Multiple possible variants found:

• chr2-46903009-G-T
• chr2-46903009-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_139279.6(MCFD2):​c.*2454C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.212 in 152,124 control chromosomes in the GnomAD database, including 3,931 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (3930 hom., cov: 32)
  • Exomes 𝑓: 0.33 (1 hom.)
• Consequence: MCFD2 NM_139279.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.363
• Publications: 6 publications found

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]

MCFD2-AS1 (HGNC:58223):

LINC01118 (HGNC:49261): (long intergenic non-protein coding RNA 1118)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 2-46903009-G-T is Benign according to our data. Variant chr2-46903009-G-T is described in ClinVar as Benign. ClinVar VariationId is 336338.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.267 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_139279.6. 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
	MCFD2	NM_139279.6	MANE Select	c.*2454C>A		3_prime_UTR	Exon 4 of 4	NP_644808.1	Q8NI22-1
	MCFD2	NM_001171506.2		c.*2454C>A		3_prime_UTR	Exon 5 of 5	NP_001164977.1	Q8NI22-1
	MCFD2	NM_001171507.2		c.*2454C>A		3_prime_UTR	Exon 4 of 4	NP_001164978.1	Q8NI22-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCFD2	ENST00000319466.9	TSL:1 MANE Select	c.*2454C>A		3_prime_UTR	Exon 4 of 4	ENSP00000317271.4	Q8NI22-1
	MCFD2	ENST00000409913.5	TSL:1	c.*2454C>A		3_prime_UTR	Exon 3 of 3	ENSP00000386941.1	Q8NI22-2
	MCFD2	ENST00000409105.5	TSL:5	c.*2454C>A		3_prime_UTR	Exon 5 of 5	ENSP00000386651.1	Q8NI22-1

Frequencies

GnomAD3 genomes AF: 0.212 AC: 32184 AN: 152000 Hom.: 3933 Cov.: 32

Gnomad AFR AF: 0.106

Gnomad AMI AF: 0.414

Gnomad AMR AF: 0.149

Gnomad ASJ AF: 0.197

Gnomad EAS AF: 0.178

Gnomad SAS AF: 0.246

Gnomad FIN AF: 0.331

Gnomad MID AF: 0.180

Gnomad NFE AF: 0.270

Gnomad OTH AF: 0.204

GnomAD4 exome AF: 0.333 AC: 2 AN: 6 Hom.: 1 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 4

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.333 AC: 2 AN: 6

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.212 AC: 32186 AN: 152118 Hom.: 3930 Cov.: 32 AF XY: 0.214 AC XY: 15898 AN XY: 74370

African (AFR) AF: 0.106 AC: 4411 AN: 41524

American (AMR) AF: 0.149 AC: 2272 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.197 AC: 682 AN: 3466

East Asian (EAS) AF: 0.177 AC: 914 AN: 5174

South Asian (SAS) AF: 0.246 AC: 1186 AN: 4820

European-Finnish (FIN) AF: 0.331 AC: 3501 AN: 10566

Middle Eastern (MID) AF: 0.194 AC: 57 AN: 294

European-Non Finnish (NFE) AF: 0.270 AC: 18358 AN: 67982

Other (OTH) AF: 0.204 AC: 429 AN: 2108

Alfa AF: 0.242 Hom.: 1636

Bravo AF: 0.192

Asia WGS AF: 0.200 AC: 695 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Factor 5 and Factor VIII, combined deficiency of, 2 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.3
DANN	Benign	0.80
PhyloP100		0.36
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs1051317; hg19: chr2-47130148;