chr2-46917393-T-C

Position:

• chr2-46917393-T-C

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.82+116T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0402 in 576,110 control chromosomes in the GnomAD database, including 944 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.055 (377 hom., cov: 32)
  • Exomes 𝑓: 0.035 (567 hom.)
• Consequence: TTC7A NM_001288953.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.317

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=-0.92).
• BP6: Variant 2-46917393-T-C is Benign according to our data. Variant chr2-46917393-T-C is described in ClinVar as [Benign]. Clinvar id is 1280667.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.108 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MCFD2	NM_001171508.2	c.-6-8216A>G		intron_variant			NP_001164979.1
MCFD2	NM_001171511.3	c.93-9424A>G		intron_variant			NP_001164982.1
TTC7A	NM_001288953.2	c.82+116T>C		intron_variant			NP_001275882.1
TTC7A	XM_047445148.1	c.-81+816T>C		intron_variant			XP_047301104.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MCFD2	ENST00000409147.1	c.-7-9424A>G		intron_variant		2		ENSP00000387082
MCFD2	ENST00000409207.5	c.-6-8216A>G		intron_variant		2		ENSP00000386386	P1
TTC7A	ENST00000409245.5	c.82+116T>C		intron_variant		2		ENSP00000386307

Frequencies

GnomAD3 genomes AF: 0.0549 AC: 8348 AN: 152086 Hom.: 375 Cov.: 32

Gnomad AFR AF: 0.110

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.0804

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.0938

Gnomad SAS AF: 0.0516

Gnomad FIN AF: 0.0421

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0187

Gnomad OTH AF: 0.0402

GnomAD4 exome AF: 0.0348 AC: 14764 AN: 423906 Hom.: 567 AF XY: 0.0345 AC XY: 7684 AN XY: 223044

Gnomad4 AFR exome AF: 0.106

Gnomad4 AMR exome AF: 0.0969

Gnomad4 ASJ exome AF: 0.00468

Gnomad4 EAS exome AF: 0.125

Gnomad4 SAS exome AF: 0.0458

Gnomad4 FIN exome AF: 0.0325

Gnomad4 NFE exome AF: 0.0190

Gnomad4 OTH exome AF: 0.0338

GnomAD4 genome AF: 0.0550 AC: 8375 AN: 152204 Hom.: 377 Cov.: 32 AF XY: 0.0570 AC XY: 4241 AN XY: 74446

Gnomad4 AFR AF: 0.110

Gnomad4 AMR AF: 0.0802

Gnomad4 ASJ AF: 0.00259

Gnomad4 EAS AF: 0.0942

Gnomad4 SAS AF: 0.0518

Gnomad4 FIN AF: 0.0421

Gnomad4 NFE AF: 0.0187

Gnomad4 OTH AF: 0.0393

Alfa AF: 0.0338 Hom.: 51

Bravo AF: 0.0612

Asia WGS AF: 0.0840 AC: 292 AN: 3478

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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	2.0
DANN	Benign	0.54

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs6715620; hg19: chr2-47144532; COSMIC: COSV60177825; COSMIC: COSV60177825;