NM_001288953.2:c.-12-153A>C

Variant names:

• chr2-46917031-A-C
• rs35134599
• NM_001288953.2:c.-12-153A>C

Variant summary

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

The NM_001288953.2(TTC7A):​c.-12-153A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0408 in 152,256 control chromosomes in the GnomAD database, including 179 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.041 (179 hom., cov: 32)
• Consequence: TTC7A NM_001288953.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0790
• Publications: 0 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 2-46917031-A-C is Benign according to our data. Variant chr2-46917031-A-C is described in ClinVar as Benign. ClinVar VariationId is 1285754.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0576 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.-12-153A>C		intron	N/A	NP_001275882.1	G5E9G4
	MCFD2	NM_001171508.2		c.-6-7854T>G		intron	N/A	NP_001164979.1	Q8NI22-1
	MCFD2	NM_001171511.3		c.93-9062T>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.-12-153A>C		intron	N/A	ENSP00000386307.1	G5E9G4
	MCFD2	ENST00000409207.5	TSL:2	c.-6-7854T>G		intron	N/A	ENSP00000386386.1	Q8NI22-1
	MCFD2	ENST00000895741.1		c.-100-6158T>G		intron	N/A	ENSP00000565800.1

Frequencies

GnomAD3 genomes AF: 0.0408 AC: 6211 AN: 152138 Hom.: 179 Cov.: 32

Gnomad AFR AF: 0.0140

Gnomad AMI AF: 0.0340

Gnomad AMR AF: 0.0392

Gnomad ASJ AF: 0.0893

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0122

Gnomad FIN AF: 0.0462

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.0591

Gnomad OTH AF: 0.0450

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

GnomAD4 genome AF: 0.0408 AC: 6210 AN: 152256 Hom.: 179 Cov.: 32 AF XY: 0.0394 AC XY: 2932 AN XY: 74444

African (AFR) AF: 0.0140 AC: 581 AN: 41560

American (AMR) AF: 0.0391 AC: 598 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0893 AC: 310 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

South Asian (SAS) AF: 0.0124 AC: 60 AN: 4826

European-Finnish (FIN) AF: 0.0462 AC: 490 AN: 10608

Middle Eastern (MID) AF: 0.0884 AC: 26 AN: 294

European-Non Finnish (NFE) AF: 0.0591 AC: 4018 AN: 68004

Other (OTH) AF: 0.0450 AC: 95 AN: 2110

Alfa AF: 0.0448 Hom.: 29

Bravo AF: 0.0407

Asia WGS AF: 0.0110 AC: 39 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	4.8
DANN	Benign	0.34
PhyloP100		-0.079
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs35134599; hg19: chr2-47144170;