2-46941573-T-C

Variant names:

• chr2-46941573-T-C
• NM_020458.4:c.32T>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_020458.4(TTC7A):​c.32T>C​(p.Leu11Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000142 in 1,405,354 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. L11L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TTC7A NM_020458.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.27
• Publications: 0 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, Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp
• combined deficiency of factor V and factor VIII

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.32T>C	p.Leu11Pro	missense	Exon 1 of 20	NP_065191.2	Q9ULT0-1
	TTC7A	NM_001288951.2		c.32T>C	p.Leu11Pro	missense	Exon 1 of 21	NP_001275880.1	Q9ULT0-4
	MCFD2	NM_001171508.2		c.-8A>G		splice_region	Exon 1 of 4	NP_001164979.1	Q8NI22-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTC7A	ENST00000319190.11	TSL:2 MANE Select	c.32T>C	p.Leu11Pro	missense	Exon 1 of 20	ENSP00000316699.5	Q9ULT0-1
	TTC7A	ENST00000394850.6	TSL:1	c.32T>C	p.Leu11Pro	missense	Exon 1 of 21	ENSP00000378320.2	Q9ULT0-4
	TTC7A	ENST00000441914.5	TSL:1	n.29T>C		non_coding_transcript_exon	Exon 1 of 19	ENSP00000393022.1	H7C055

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000142 AC: 2 AN: 1405354 Hom.: 0 Cov.: 31 AF XY: 0.00000144 AC XY: 1 AN XY: 693958

African (AFR) AF: 0.00 AC: 0 AN: 31938

American (AMR) AF: 0.00 AC: 0 AN: 36844

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25220

East Asian (EAS) AF: 0.00 AC: 0 AN: 36362

South Asian (SAS) AF: 0.00 AC: 0 AN: 79678

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48076

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5658

European-Non Finnish (NFE) AF: 0.00000185 AC: 2 AN: 1083334

Other (OTH) AF: 0.00 AC: 0 AN: 58244

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	1	-	TTC7A-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.70	T
M_CAP	Pathogenic	0.54	D
MetaRNN	Uncertain	0.49	T
MetaSVM	Benign	-0.42	T
PhyloP100		2.3
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-1.2	N
REVEL	Uncertain	0.52
Sift	Benign	0.038	D
Sift4G	Uncertain	0.026	D
Polyphen		0.92	P
Vest4		0.55
MutPred		0.26		Loss of stability (P = 0.0209)
MVP		0.80
MPC		0.34
ClinPred		0.99	D
GERP RS		4.0
PromoterAI		0.094	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.58
gMVP		0.64
Mutation Taster		=39/61	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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

hg19: chr2-47168712;