chr2-46940931-A-G

Position:

• chr2-46940931-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001288953.2(TTC7A):​c.83-9432A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0586 in 151,772 control chromosomes in the GnomAD database, including 322 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.059 (322 hom., cov: 32)
• Consequence: TTC7A NM_001288953.2 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -4.76

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 2-46940931-A-G is Benign according to our data. Variant chr2-46940931-A-G is described in ClinVar as [Benign]. Clinvar id is 1268387.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0907 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MCFD2	NM_001171508.2	c.-7+641T>C		intron_variant			NP_001164979.1
MCFD2	NM_001171511.3	c.92+641T>C		intron_variant			NP_001164982.1
TTC7A	NM_001288953.2	c.83-9432A>G		intron_variant			NP_001275882.1
TTC7A	XM_047445148.1	c.-80-9432A>G		intron_variant			XP_047301104.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MCFD2	ENST00000409147.1	c.-8+641T>C		intron_variant		2		ENSP00000387082
MCFD2	ENST00000409207.5	c.-7+641T>C		intron_variant		2		ENSP00000386386	P1
TTC7A	ENST00000409245.5	c.83-9432A>G		intron_variant		2		ENSP00000386307

Frequencies

GnomAD3 genomes AF: 0.0586 AC: 8890 AN: 151660 Hom.: 322 Cov.: 32

Gnomad AFR AF: 0.0934

Gnomad AMI AF: 0.0385

Gnomad AMR AF: 0.0388

Gnomad ASJ AF: 0.0655

Gnomad EAS AF: 0.000395

Gnomad SAS AF: 0.00884

Gnomad FIN AF: 0.0326

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0534

Gnomad OTH AF: 0.0712

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0586 AC: 8889 AN: 151772 Hom.: 322 Cov.: 32 AF XY: 0.0562 AC XY: 4172 AN XY: 74188

Gnomad4 AFR AF: 0.0932

Gnomad4 AMR AF: 0.0388

Gnomad4 ASJ AF: 0.0655

Gnomad4 EAS AF: 0.000396

Gnomad4 SAS AF: 0.00842

Gnomad4 FIN AF: 0.0326

Gnomad4 NFE AF: 0.0534

Gnomad4 OTH AF: 0.0705

Alfa AF: 0.0192 Hom.: 7

Bravo AF: 0.0608

Asia WGS AF: 0.0140 AC: 49 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 09, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	7.3
DANN	Benign	0.57

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs4314044; hg19: chr2-47168070;