chr2-46940847-T-C

Variant names:

• chr2-46940847-T-C
• rs4583513
• NM_001288953.2:c.83-9516T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001288953.2(TTC7A):​c.83-9516T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0585 in 152,044 control chromosomes in the GnomAD database, including 324 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.059 (324 hom., cov: 32)
• Consequence: TTC7A NM_001288953.2 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -5.25
• Publications: 1 publications found

Genes affected

TTC7A (HGNC:19750): (tetratricopeptide repeat domain 7A) This gene encodes a protein containing tetratricopeptide repeats. Mutations in this gene disrupt intestinal development and can cause early onset inflammatory bowel disease and intestinal atresia. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jun 2014]

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 Gene-Disease associations (from GenCC):

• factor 5 and Factor VIII, combined deficiency of, 2

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp
• combined deficiency of factor V and factor VIII

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 2-46940847-T-C is Benign according to our data. Variant chr2-46940847-T-C is described in ClinVar as Benign. ClinVar VariationId is 1271947.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0907 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001288953.2. 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
	TTC7A	NM_001288953.2		c.83-9516T>C		intron	N/A	NP_001275882.1	G5E9G4
	MCFD2	NM_001171508.2		c.-7+725A>G		intron	N/A	NP_001164979.1	Q8NI22-1
	MCFD2	NM_001171511.3		c.92+725A>G		intron	N/A	NP_001164982.1	Q8NI22-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTC7A	ENST00000409245.5	TSL:2	c.83-9516T>C		intron	N/A	ENSP00000386307.1	G5E9G4
	MCFD2	ENST00000409207.5	TSL:2	c.-7+725A>G		intron	N/A	ENSP00000386386.1	Q8NI22-1
	MCFD2	ENST00000895741.1		c.-101+725A>G		intron	N/A	ENSP00000565800.1

Frequencies

GnomAD3 genomes AF: 0.0586 AC: 8899 AN: 151926 Hom.: 324 Cov.: 32

Gnomad AFR AF: 0.0934

Gnomad AMI AF: 0.0384

Gnomad AMR AF: 0.0388

Gnomad ASJ AF: 0.0657

Gnomad EAS AF: 0.000391

Gnomad SAS AF: 0.00870

Gnomad FIN AF: 0.0327

Gnomad MID AF: 0.0318

Gnomad NFE AF: 0.0534

Gnomad OTH AF: 0.0718

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0585 AC: 8898 AN: 152044 Hom.: 324 Cov.: 32 AF XY: 0.0562 AC XY: 4175 AN XY: 74300

African (AFR) AF: 0.0931 AC: 3864 AN: 41492

American (AMR) AF: 0.0387 AC: 592 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0657 AC: 228 AN: 3470

East Asian (EAS) AF: 0.000392 AC: 2 AN: 5106

South Asian (SAS) AF: 0.00829 AC: 40 AN: 4826

European-Finnish (FIN) AF: 0.0327 AC: 346 AN: 10584

Middle Eastern (MID) AF: 0.0308 AC: 9 AN: 292

European-Non Finnish (NFE) AF: 0.0534 AC: 3632 AN: 67956

Other (OTH) AF: 0.0710 AC: 150 AN: 2112

Alfa AF: 0.0577 Hom.: 32

Bravo AF: 0.0608

Asia WGS AF: 0.0150 AC: 51 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.0
DANN	Benign	0.44
PhyloP100		-5.3
PromoterAI		-0.19	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs4583513; hg19: chr2-47167986;