2-46941717-C-G

Variant names:

• chr2-46941717-C-G
• rs201805434
• NM_020458.4:c.176C>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_020458.4(TTC7A):​c.176C>G​(p.Pro59Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00535 in 1,550,222 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0032 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0056 (25 hom.)
• Consequence: TTC7A NM_020458.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: -1.02
• Publications: 7 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, Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• combined deficiency of factor V and factor VIII

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0039743185).
• BP6: Variant 2-46941717-C-G is Benign according to our data. Variant chr2-46941717-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 528474.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00316 (482/152354) while in subpopulation NFE AF = 0.00535 (364/68036). AF 95% confidence interval is 0.0049. There are 0 homozygotes in GnomAd4. There are 195 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 25 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020458.4. 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_020458.4	MANE Select	c.176C>G	p.Pro59Arg	missense	Exon 1 of 20	NP_065191.2
	TTC7A	NM_001288951.2		c.176C>G	p.Pro59Arg	missense	Exon 1 of 21	NP_001275880.1
	TTC7A	NM_001288955.2		c.-729C>G		5_prime_UTR	Exon 1 of 19	NP_001275884.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTC7A	ENST00000319190.11	TSL:2 MANE Select	c.176C>G	p.Pro59Arg	missense	Exon 1 of 20	ENSP00000316699.5
	TTC7A	ENST00000394850.6	TSL:1	c.176C>G	p.Pro59Arg	missense	Exon 1 of 21	ENSP00000378320.2
	TTC7A	ENST00000441914.5	TSL:1	n.173C>G		non_coding_transcript_exon	Exon 1 of 19	ENSP00000393022.1

Frequencies

GnomAD3 genomes AF: 0.00317 AC: 482 AN: 152236 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00106

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00227

Gnomad FIN AF: 0.000470

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00535

Gnomad OTH AF: 0.00526

GnomAD2 exomes AF: 0.00352 AC: 501 AN: 142200 AF XY: 0.00362

Gnomad AFR exome AF: 0.000717

Gnomad AMR exome AF: 0.00188

Gnomad ASJ exome AF: 0.00477

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000393

Gnomad NFE exome AF: 0.00646

Gnomad OTH exome AF: 0.00669

GnomAD4 exome AF: 0.00559 AC: 7817 AN: 1397868 Hom.: 25 Cov.: 31 AF XY: 0.00551 AC XY: 3802 AN XY: 689512

African (AFR) AF: 0.000379 AC: 12 AN: 31630

American (AMR) AF: 0.00213 AC: 76 AN: 35728

Ashkenazi Jewish (ASJ) AF: 0.00600 AC: 151 AN: 25152

East Asian (EAS) AF: 0.00 AC: 0 AN: 35818

South Asian (SAS) AF: 0.00288 AC: 228 AN: 79214

European-Finnish (FIN) AF: 0.000565 AC: 27 AN: 47788

Middle Eastern (MID) AF: 0.00200 AC: 11 AN: 5498

European-Non Finnish (NFE) AF: 0.00650 AC: 7012 AN: 1079078

Other (OTH) AF: 0.00518 AC: 300 AN: 57962

GnomAD4 genome AF: 0.00316 AC: 482 AN: 152354 Hom.: 0 Cov.: 32 AF XY: 0.00262 AC XY: 195 AN XY: 74506

African (AFR) AF: 0.00106 AC: 44 AN: 41582

American (AMR) AF: 0.00183 AC: 28 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00403 AC: 14 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00228 AC: 11 AN: 4832

European-Finnish (FIN) AF: 0.000470 AC: 5 AN: 10632

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00535 AC: 364 AN: 68036

Other (OTH) AF: 0.00520 AC: 11 AN: 2114

Alfa AF: 0.00534 Hom.: 0

Bravo AF: 0.00364

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00701 AC: 27

ExAC AF: 0.00176 AC: 156

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	1	-	Gastrointestinal defects and immunodeficiency syndrome 1 (1)
-	-	1	Multiple gastrointestinal atresias (1)
-	-	1	TTC7A-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	2.1
DANN	Benign	0.74
DEOGEN2	Benign	0.047	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.53	T
MetaRNN	Benign	0.0040	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
PhyloP100		-1.0
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.78	N
REVEL	Benign	0.021
Sift	Benign	0.80	T
Sift4G	Benign	0.37	T
Polyphen		0.0030	B
Vest4		0.050
MVP		0.15
MPC		0.066
ClinPred		0.0086	T
GERP RS		-6.7
PromoterAI		-0.14	Neutral
Varity_R		0.052
gMVP		0.16
Mutation Taster		=299/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs201805434; hg19: chr2-47168856; COSMIC: COSV55411080; COSMIC: COSV55411080;