chr11-59864062-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001062.4(TCN1):c.104G>A(p.Arg35His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0372 in 1,613,558 control chromosomes in the GnomAD database, including 1,360 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.032 ( 124 hom., cov: 32)

Exomes 𝑓: 0.038 ( 1236 hom. )

Consequence

TCN1
NM_001062.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -3.05

Publications

25 publications found

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]

TCN1 Gene-Disease associations (from GenCC):

transcobalamin I deficiency
Inheritance: AR Classification: MODERATE Submitted by: PanelApp Australia

TCN1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008763701).

BP6

Variant 11-59864062-C-T is Benign according to our data. Variant chr11-59864062-C-T is described in ClinVar as Benign. ClinVar VariationId is 460313.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0318 (4841/152112) while in subpopulation NFE AF = 0.0422 (2866/67962). AF 95% confidence interval is 0.0409. There are 124 homozygotes in GnomAd4. There are 2372 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 124 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001062.4. 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
	TCN1	NM_001062.4	MANE Select	c.104G>A	p.Arg35His	missense	Exon 2 of 9	NP_001053.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TCN1	ENST00000257264.4	TSL:1 MANE Select	c.104G>A	p.Arg35His	missense	Exon 2 of 9	ENSP00000257264.3	P20061
TCN1	ENST00000532419.5	TSL:5	n.123G>A		non_coding_transcript_exon	Exon 2 of 5
TCN1	ENST00000534531.1	TSL:5	n.81-1340G>A		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.0319

AC:

4842

AN:

151994

Hom.:

124

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00725

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.0413

Gnomad ASJ

AF:

0.101

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.00810

Gnomad FIN

AF:

0.0528

Gnomad MID

AF:

0.0538

Gnomad NFE

AF:

0.0422

Gnomad OTH

AF:

0.0374

GnomAD2 exomes

AF:

0.0344

AC:

8640

AN:

251102

AF XY:

0.0346

show subpopulations

Gnomad AFR exome

AF:

0.00566

Gnomad AMR exome

AF:

0.0273

Gnomad ASJ exome

AF:

0.0995

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.0549

Gnomad NFE exome

AF:

0.0430

Gnomad OTH exome

AF:

0.0395

GnomAD4 exome

AF:

0.0377

AC:

55109

AN:

1461446

Hom.:

1236

Cov.:

AF XY:

0.0375

AC XY:

27260

AN XY:

727036

show subpopulations

African (AFR)

AF:

0.00571

AC:

191

AN:

33470

American (AMR)

AF:

0.0275

AC:

1230

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0988

AC:

2580

AN:

26118

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39694

South Asian (SAS)

AF:

0.00931

AC:

803

AN:

86250

European-Finnish (FIN)

AF:

0.0569

AC:

3038

AN:

53408

Middle Eastern (MID)

AF:

0.0437

AC:

252

AN:

5766

European-Non Finnish (NFE)

AF:

0.0403

AC:

44745

AN:

1111634

Other (OTH)

AF:

0.0376

AC:

2268

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.452

Heterozygous variant carriers

2920

5840

8761

11681

14601

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1616

3232

4848

6464

8080

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0318

AC:

4841

AN:

152112

Hom.:

124

Cov.:

AF XY:

0.0319

AC XY:

2372

AN XY:

74360

show subpopulations

African (AFR)

AF:

0.00722

AC:

300

AN:

41528

American (AMR)

AF:

0.0413

AC:

631

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.101

AC:

349

AN:

3470

East Asian (EAS)

AF:

0.000386

AC:

AN:

5176

South Asian (SAS)

AF:

0.00810

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.0528

AC:

559

AN:

10588

Middle Eastern (MID)

AF:

0.0510

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0422

AC:

2866

AN:

67962

Other (OTH)

AF:

0.0370

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

237

474

710

947

1184

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

168

224

280

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0398

Hom.:

319

Bravo

AF:

0.0305

TwinsUK

AF:

0.0405

AC:

150

ALSPAC

AF:

0.0451

AC:

174

ESP6500AA

AF:

0.00841

AC:

ESP6500EA

AF:

0.0406

AC:

349

ExAC

AF:

0.0325

AC:

3942

Asia WGS

AF:

0.00693

AC:

AN:

3478

EpiCase

AF:

0.0483

EpiControl

AF:

0.0472

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Transcobalamin I deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.76

BayesDel_noAF

Benign

-0.83

CADD

Benign

0.048

(source)

DANN

Benign

0.67

DEOGEN2

Benign

0.021

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.0025

LIST_S2

Benign

0.41

MetaRNN

Benign

0.0088

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.72

PhyloP100

-3.0

PrimateAI

Benign

0.22

PROVEAN

Benign

-0.98

REVEL

Benign

0.015

Sift

Benign

0.60

Sift4G

Benign

0.53

Polyphen

0.012

Vest4

0.035

MPC

0.016

ClinPred

0.0052

GERP RS

-8.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.038

gMVP

0.13

Mutation Taster

=98/2

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over