2-46941458-C-A

Position:

• chr2-46941458-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_020458.4(TTC7A):​c.-84C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0309 in 1,426,564 control chromosomes in the GnomAD database, including 1,711 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.062 (545 hom., cov: 32)
  • Exomes 𝑓: 0.027 (1166 hom.)
• Consequence: TTC7A NM_020458.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.01

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 2-46941458-C-A is Benign according to our data. Variant chr2-46941458-C-A is described in ClinVar as [Benign]. Clinvar id is 1250809.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.131 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTC7A	NM_020458.4	c.-84C>A		5_prime_UTR_variant	1/20	ENST00000319190.11	NP_065191.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTC7A	ENST00000319190.11	c.-84C>A		5_prime_UTR_variant	1/20	2	NM_020458.4	ENSP00000316699	P1

Frequencies

GnomAD3 genomes AF: 0.0618 AC: 9351 AN: 151278 Hom.: 537 Cov.: 32

Gnomad AFR AF: 0.134

Gnomad AMI AF: 0.00881

Gnomad AMR AF: 0.0810

Gnomad ASJ AF: 0.00260

Gnomad EAS AF: 0.0923

Gnomad SAS AF: 0.0690

Gnomad FIN AF: 0.0417

Gnomad MID AF: 0.0162

Gnomad NFE AF: 0.0183

Gnomad OTH AF: 0.0466

GnomAD4 exome AF: 0.0272 AC: 34697 AN: 1275176 Hom.: 1166 Cov.: 28 AF XY: 0.0275 AC XY: 17149 AN XY: 623246

Gnomad4 AFR exome AF: 0.142

Gnomad4 AMR exome AF: 0.113

Gnomad4 ASJ exome AF: 0.00516

Gnomad4 EAS exome AF: 0.126

Gnomad4 SAS exome AF: 0.0650

Gnomad4 FIN exome AF: 0.0350

Gnomad4 NFE exome AF: 0.0169

Gnomad4 OTH exome AF: 0.0326

GnomAD4 genome AF: 0.0620 AC: 9387 AN: 151388 Hom.: 545 Cov.: 32 AF XY: 0.0638 AC XY: 4722 AN XY: 74014

Gnomad4 AFR AF: 0.134

Gnomad4 AMR AF: 0.0809

Gnomad4 ASJ AF: 0.00260

Gnomad4 EAS AF: 0.0926

Gnomad4 SAS AF: 0.0693

Gnomad4 FIN AF: 0.0417

Gnomad4 NFE AF: 0.0183

Gnomad4 OTH AF: 0.0456

Alfa AF: 0.0431 Hom.: 46

Bravo AF: 0.0689

Asia WGS AF: 0.0940 AC: 325 AN: 3470

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	-0.53
CADD	Benign	8.1
DANN	Benign	0.92
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs140303915; hg19: chr2-47168597;