chr11-59853244-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001062.4(TCN1):​c.1199C>T​(p.Thr400Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000198 in 1,613,938 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

TCN1
NM_001062.4 missense

Scores

6
13

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.60
Variant links:
Genes affected
TCN1 (HGNC:11652): (transcobalamin 1) This gene encodes a member of the vitamin B12-binding protein family. This family of proteins, alternatively referred to as R binders, is expressed in various tissues and secretions. This protein is a major constituent of secondary granules in neutrophils and facilitates the transport of cobalamin into cells. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
TCN1NM_001062.4 linkuse as main transcriptc.1199C>T p.Thr400Ile missense_variant 8/9 ENST00000257264.4 NP_001053.2 P20061

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
TCN1ENST00000257264.4 linkuse as main transcriptc.1199C>T p.Thr400Ile missense_variant 8/91 NM_001062.4 ENSP00000257264.3 P20061
TCN1ENST00000529251.1 linkuse as main transcriptn.198C>T non_coding_transcript_exon_variant 2/33

Frequencies

GnomAD3 genomes
AF:
0.00000658
AC:
1
AN:
152058
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000119
AC:
3
AN:
251286
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135810
show subpopulations
Gnomad AFR exome
AF:
0.0000615
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000176
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000212
AC:
31
AN:
1461880
Hom.:
0
Cov.:
31
AF XY:
0.0000234
AC XY:
17
AN XY:
727246
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000252
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.00000658
AC:
1
AN:
152058
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74260
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.00
AC:
0
ExAC
AF:
0.0000165
AC:
2
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJun 05, 2024The c.1199C>T (p.T400I) alteration is located in exon 8 (coding exon 8) of the TCN1 gene. This alteration results from a C to T substitution at nucleotide position 1199, causing the threonine (T) at amino acid position 400 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.40
BayesDel_addAF
Benign
-0.22
T
BayesDel_noAF
Benign
-0.37
CADD
Benign
21
DANN
Uncertain
1.0
DEOGEN2
Benign
0.23
T
Eigen
Uncertain
0.22
Eigen_PC
Benign
0.20
FATHMM_MKL
Benign
0.66
D
LIST_S2
Benign
0.74
T
M_CAP
Benign
0.0096
T
MetaRNN
Uncertain
0.45
T
MetaSVM
Benign
-0.99
T
MutationAssessor
Uncertain
2.6
M
PrimateAI
Benign
0.48
T
PROVEAN
Uncertain
-4.3
D
REVEL
Benign
0.18
Sift
Benign
0.084
T
Sift4G
Benign
0.17
T
Polyphen
0.90
P
Vest4
0.45
MutPred
0.56
Gain of catalytic residue at L405 (P = 0.0634);
MVP
0.46
MPC
0.12
ClinPred
0.98
D
GERP RS
4.0
Varity_R
0.38
gMVP
0.53

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs780762247; hg19: chr11-59620717; API