2-46917064-C-G

Position:

• chr2-46917064-C-G

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.-12-120C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0887 in 643,898 control chromosomes in the GnomAD database, including 3,680 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1734 hom., cov: 32)
  • Exomes 𝑓: 0.077 (1946 hom.)
• Consequence: TTC7A NM_001288953.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.26

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=-0.98).
• BP6: Variant 2-46917064-C-G is Benign according to our data. Variant chr2-46917064-C-G is described in ClinVar as [Benign]. Clinvar id is 1249964.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.25 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MCFD2	NM_001171508.2	c.-6-7887G>C		intron_variant			NP_001164979.1
MCFD2	NM_001171511.3	c.93-9095G>C		intron_variant			NP_001164982.1
TTC7A	NM_001288953.2	c.-12-120C>G		intron_variant			NP_001275882.1
TTC7A	XM_047445148.1	c.-81+487C>G		intron_variant			XP_047301104.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MCFD2	ENST00000409147.1	c.-7-9095G>C		intron_variant		2		ENSP00000387082
MCFD2	ENST00000409207.5	c.-6-7887G>C		intron_variant		2		ENSP00000386386	P1
TTC7A	ENST00000409245.5	c.-12-120C>G		intron_variant		2		ENSP00000386307

Frequencies

GnomAD3 genomes AF: 0.125 AC: 19002 AN: 152072 Hom.: 1724 Cov.: 32

Gnomad AFR AF: 0.254

Gnomad AMI AF: 0.0921

Gnomad AMR AF: 0.121

Gnomad ASJ AF: 0.0685

Gnomad EAS AF: 0.0946

Gnomad SAS AF: 0.0597

Gnomad FIN AF: 0.0743

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0662

Gnomad OTH AF: 0.121

GnomAD4 exome AF: 0.0775 AC: 38097 AN: 491708 Hom.: 1946 AF XY: 0.0748 AC XY: 19885 AN XY: 265990

Gnomad4 AFR exome AF: 0.256

Gnomad4 AMR exome AF: 0.132

Gnomad4 ASJ exome AF: 0.0679

Gnomad4 EAS exome AF: 0.123

Gnomad4 SAS exome AF: 0.0569

Gnomad4 FIN exome AF: 0.0615

Gnomad4 NFE exome AF: 0.0658

Gnomad4 OTH exome AF: 0.0817

GnomAD4 genome AF: 0.125 AC: 19048 AN: 152190 Hom.: 1734 Cov.: 32 AF XY: 0.125 AC XY: 9306 AN XY: 74406

Gnomad4 AFR AF: 0.254

Gnomad4 AMR AF: 0.121

Gnomad4 ASJ AF: 0.0685

Gnomad4 EAS AF: 0.0950

Gnomad4 SAS AF: 0.0595

Gnomad4 FIN AF: 0.0743

Gnomad4 NFE AF: 0.0662

Gnomad4 OTH AF: 0.120

Alfa AF: 0.0306 Hom.: 24

Bravo AF: 0.136

Asia WGS AF: 0.103 AC: 358 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 09, 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	-0.98
CADD	Benign	0.76
DANN	Benign	0.40

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs13388612; hg19: chr2-47144203; COSMIC: COSV60177819; COSMIC: COSV60177819;