2-46917255-C-G

Position:

• chr2-46917255-C-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001288953.2(TTC7A):​c.60C>G​(p.Leu20=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0358 in 699,252 control chromosomes in the GnomAD database, including 578 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.033 (103 hom., cov: 32)
  • Exomes 𝑓: 0.037 (475 hom.)
• Consequence: TTC7A NM_001288953.2 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.22

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 2-46917255-C-G is Benign according to our data. Variant chr2-46917255-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 1209045.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.22 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0334 (5088/152182) while in subpopulation NFE AF= 0.0473 (3217/67988). AF 95% confidence interval is 0.046. There are 103 homozygotes in gnomad4. There are 2399 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 103 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTC7A	NM_001288953.2	c.60C>G	p.Leu20=	synonymous_variant	2/21		NP_001275882.1
MCFD2	NM_001171508.2	c.-6-8078G>C		intron_variant			NP_001164979.1
MCFD2	NM_001171511.3	c.93-9286G>C		intron_variant			NP_001164982.1
TTC7A	XM_047445148.1	c.-81+678C>G		intron_variant			XP_047301104.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTC7A	ENST00000409245.5	c.60C>G	p.Leu20=	synonymous_variant	2/21	2		ENSP00000386307
MCFD2	ENST00000409147.1	c.-7-9286G>C		intron_variant		2		ENSP00000387082
MCFD2	ENST00000409207.5	c.-6-8078G>C		intron_variant		2		ENSP00000386386	P1

Frequencies

GnomAD3 genomes AF: 0.0335 AC: 5089 AN: 152064 Hom.: 103 Cov.: 32

Gnomad AFR AF: 0.0161

Gnomad AMI AF: 0.0779

Gnomad AMR AF: 0.0269

Gnomad ASJ AF: 0.0660

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00870

Gnomad FIN AF: 0.0324

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0473

Gnomad OTH AF: 0.0478

GnomAD3 exomes AF: 0.0315 AC: 4092 AN: 129806 Hom.: 102 AF XY: 0.0315 AC XY: 2243 AN XY: 71186

Gnomad AFR exome AF: 0.0154

Gnomad AMR exome AF: 0.0215

Gnomad ASJ exome AF: 0.0634

Gnomad EAS exome AF: 0.0000993

Gnomad SAS exome AF: 0.0130

Gnomad FIN exome AF: 0.0255

Gnomad NFE exome AF: 0.0477

Gnomad OTH exome AF: 0.0387

GnomAD4 exome AF: 0.0365 AC: 19980 AN: 547070 Hom.: 475 Cov.: 0 AF XY: 0.0357 AC XY: 10579 AN XY: 296248

Gnomad4 AFR exome AF: 0.0170

Gnomad4 AMR exome AF: 0.0225

Gnomad4 ASJ exome AF: 0.0620

Gnomad4 EAS exome AF: 0.0000937

Gnomad4 SAS exome AF: 0.0121

Gnomad4 FIN exome AF: 0.0286

Gnomad4 NFE exome AF: 0.0466

Gnomad4 OTH exome AF: 0.0374

GnomAD4 genome AF: 0.0334 AC: 5088 AN: 152182 Hom.: 103 Cov.: 32 AF XY: 0.0322 AC XY: 2399 AN XY: 74394

Gnomad4 AFR AF: 0.0160

Gnomad4 AMR AF: 0.0269

Gnomad4 ASJ AF: 0.0660

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.00830

Gnomad4 FIN AF: 0.0324

Gnomad4 NFE AF: 0.0473

Gnomad4 OTH AF: 0.0473

Alfa AF: 0.0268 Hom.: 20

Bravo AF: 0.0326

Asia WGS AF: 0.0100 AC: 36 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 10, 2018	- -

TTC7A-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 06, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.34
DANN	Benign	0.76

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs76192704; hg19: chr2-47144394;