rs6754439

Variant names:

• chr2-46941188-C-A
• rs6754439
• NM_001288953.2:c.83-9175C>A

Your query was ambiguous. Multiple possible variants found:

• chr2-46941188-C-A
• chr2-46941188-C-T

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.83-9175C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0482 in 147,432 control chromosomes in the GnomAD database, including 277 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.048 (272 hom., cov: 32)
  • Exomes 𝑓: 0.055 (5 hom.)
• Consequence: TTC7A NM_001288953.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.294
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 2-46941188-C-A is Benign according to our data. Variant chr2-46941188-C-A is described in ClinVar as Benign. ClinVar VariationId is 1274211.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0841 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.83-9175C>A		intron	N/A	NP_001275882.1	G5E9G4
	MCFD2	NM_001171508.2		c.-7+384G>T		intron	N/A	NP_001164979.1	Q8NI22-1
	MCFD2	NM_001171511.3		c.92+384G>T		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.83-9175C>A		intron	N/A	ENSP00000386307.1	G5E9G4
	MCFD2	ENST00000409207.5	TSL:2	c.-7+384G>T		intron	N/A	ENSP00000386386.1	Q8NI22-1
	MCFD2	ENST00000895741.1		c.-101+384G>T		intron	N/A	ENSP00000565800.1

Frequencies

GnomAD3 genomes AF: 0.0481 AC: 7029 AN: 146188 Hom.: 270 Cov.: 32

Gnomad AFR AF: 0.0850

Gnomad AMI AF: 0.00897

Gnomad AMR AF: 0.0772

Gnomad ASJ AF: 0.00267

Gnomad EAS AF: 0.0907

Gnomad SAS AF: 0.0689

Gnomad FIN AF: 0.0431

Gnomad MID AF: 0.0163

Gnomad NFE AF: 0.0180

Gnomad OTH AF: 0.0367

GnomAD4 exome AF: 0.0546 AC: 62 AN: 1136 Hom.: 5 Cov.: 0 AF XY: 0.0537 AC XY: 33 AN XY: 614

African (AFR) AF: 0.00 AC: 0 AN: 6

American (AMR) AF: 0.00 AC: 0 AN: 8

Ashkenazi Jewish (ASJ) AF: 0.167 AC: 1 AN: 6

East Asian (EAS) AF: 0.250 AC: 3 AN: 12

South Asian (SAS) AF: 0.0606 AC: 51 AN: 842

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 14

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4

European-Non Finnish (NFE) AF: 0.0256 AC: 6 AN: 234

Other (OTH) AF: 0.100 AC: 1 AN: 10

GnomAD4 genome AF: 0.0482 AC: 7047 AN: 146296 Hom.: 272 Cov.: 32 AF XY: 0.0503 AC XY: 3585 AN XY: 71226

African (AFR) AF: 0.0852 AC: 3469 AN: 40730

American (AMR) AF: 0.0771 AC: 1141 AN: 14804

Ashkenazi Jewish (ASJ) AF: 0.00267 AC: 9 AN: 3374

East Asian (EAS) AF: 0.0910 AC: 453 AN: 4976

South Asian (SAS) AF: 0.0692 AC: 331 AN: 4782

European-Finnish (FIN) AF: 0.0431 AC: 376 AN: 8732

Middle Eastern (MID) AF: 0.0175 AC: 5 AN: 286

European-Non Finnish (NFE) AF: 0.0180 AC: 1182 AN: 65680

Other (OTH) AF: 0.0358 AC: 73 AN: 2040

Alfa AF: 0.0123 Hom.: 7

Asia WGS AF: 0.0930 AC: 268 AN: 2884

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	-0.55
CADD	Benign	16
DANN	Benign	0.93
PhyloP100		0.29
PromoterAI		0.0070	Neutral
Mutation Taster		=300/0	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: rs6754439; hg19: chr2-47168327;