2-46941188-C-A

Position:

• chr2-46941188-C-A

Variant summary

Our verdict is Benign. Variant got -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

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]

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTC7A	NM_020458.4			upstream_gene_variant		ENST00000319190.11	NP_065191.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTC7A	ENST00000319190.11			upstream_gene_variant		2	NM_020458.4	ENSP00000316699	P1

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.167

Gnomad4 EAS exome AF: 0.250

Gnomad4 SAS exome AF: 0.0606

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0256

Gnomad4 OTH exome AF: 0.100

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

Gnomad4 AFR AF: 0.0852

Gnomad4 AMR AF: 0.0771

Gnomad4 ASJ AF: 0.00267

Gnomad4 EAS AF: 0.0910

Gnomad4 SAS AF: 0.0692

Gnomad4 FIN AF: 0.0431

Gnomad4 NFE AF: 0.0180

Gnomad4 OTH AF: 0.0358

Alfa AF: 0.0123 Hom.: 7

Asia WGS AF: 0.0930 AC: 268 AN: 2884

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 06, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	16
DANN	Benign	0.93

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

Publications

LitVar

Other links and lift over

dbSNP: rs6754439; hg19: chr2-47168327;