rs6729120

Variant names:

• chr2-46917490-A-G
• rs6729120
• NM_001288953.2:c.82+213A>G

Your query was ambiguous. Multiple possible variants found:

• chr2-46917490-A-G
• chr2-46917490-A-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.82+213A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0593 in 152,186 control chromosomes in the GnomAD database, including 459 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.059 (459 hom., cov: 32)
• Consequence: TTC7A NM_001288953.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.847
• Publications: 2 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=-0.9).
• BP6: Variant 2-46917490-A-G is Benign according to our data. Variant chr2-46917490-A-G is described in ClinVar as Benign. ClinVar VariationId is 1285856.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.122 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.82+213A>G		intron	N/A	NP_001275882.1	G5E9G4
	MCFD2	NM_001171508.2		c.-6-8313T>C		intron	N/A	NP_001164979.1	Q8NI22-1
	MCFD2	NM_001171511.3		c.93-9521T>C		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.82+213A>G		intron	N/A	ENSP00000386307.1	G5E9G4
	MCFD2	ENST00000409207.5	TSL:2	c.-6-8313T>C		intron	N/A	ENSP00000386386.1	Q8NI22-1
	MCFD2	ENST00000895741.1		c.-100-6617T>C		intron	N/A	ENSP00000565800.1

Frequencies

GnomAD3 genomes AF: 0.0592 AC: 9000 AN: 152068 Hom.: 456 Cov.: 32

Gnomad AFR AF: 0.125

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.0817

Gnomad ASJ AF: 0.00260

Gnomad EAS AF: 0.0937

Gnomad SAS AF: 0.0520

Gnomad FIN AF: 0.0424

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0188

Gnomad OTH AF: 0.0435

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

GnomAD4 genome AF: 0.0593 AC: 9028 AN: 152186 Hom.: 459 Cov.: 32 AF XY: 0.0610 AC XY: 4536 AN XY: 74402

African (AFR) AF: 0.125 AC: 5202 AN: 41504

American (AMR) AF: 0.0815 AC: 1246 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00260 AC: 9 AN: 3468

East Asian (EAS) AF: 0.0941 AC: 487 AN: 5176

South Asian (SAS) AF: 0.0522 AC: 252 AN: 4826

European-Finnish (FIN) AF: 0.0424 AC: 449 AN: 10592

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0188 AC: 1276 AN: 68012

Other (OTH) AF: 0.0425 AC: 90 AN: 2116

Alfa AF: 0.0208 Hom.: 27

Bravo AF: 0.0664

Asia WGS AF: 0.0850 AC: 296 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	-0.90
CADD	Benign	0.26
DANN	Benign	0.65
PhyloP100		-0.85
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: rs6729120; hg19: chr2-47144629; COSMIC: COSV60177817; COSMIC: COSV60177817;