11-59864062-C-T

Position:

• chr11-59864062-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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. 14/20 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -3.05

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 124 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TCN1	NM_001062.4	c.104G>A	p.Arg35His	missense_variant	2/9	ENST00000257264.4	NP_001053.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TCN1	ENST00000257264.4	c.104G>A	p.Arg35His	missense_variant	2/9	1	NM_001062.4	ENSP00000257264	P1
TCN1	ENST00000532419.5	n.123G>A		non_coding_transcript_exon_variant	2/5	5
TCN1	ENST00000534531.1	n.81-1340G>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.0319 AC: 4842 AN: 151994 Hom.: 124 Cov.: 32

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

GnomAD3 exomes AF: 0.0344 AC: 8640 AN: 251102 Hom.: 224 AF XY: 0.0346 AC XY: 4701 AN XY: 135710

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 SAS exome AF: 0.00951

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.: 32 AF XY: 0.0375 AC XY: 27260 AN XY: 727036

Gnomad4 AFR exome AF: 0.00571

Gnomad4 AMR exome AF: 0.0275

Gnomad4 ASJ exome AF: 0.0988

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00931

Gnomad4 FIN exome AF: 0.0569

Gnomad4 NFE exome AF: 0.0403

Gnomad4 OTH exome AF: 0.0376

GnomAD4 genome AF: 0.0318 AC: 4841 AN: 152112 Hom.: 124 Cov.: 32 AF XY: 0.0319 AC XY: 2372 AN XY: 74360

Gnomad4 AFR AF: 0.00722

Gnomad4 AMR AF: 0.0413

Gnomad4 ASJ AF: 0.101

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00810

Gnomad4 FIN AF: 0.0528

Gnomad4 NFE AF: 0.0422

Gnomad4 OTH AF: 0.0370

Alfa AF: 0.0416 Hom.: 242

Bravo AF: 0.0305

TwinsUK AF: 0.0405 AC: 150

ALSPAC AF: 0.0451 AC: 174

ESP6500AA AF: 0.00841 AC: 37

ESP6500EA AF: 0.0406 AC: 349

ExAC AF: 0.0325 AC: 3942

Asia WGS AF: 0.00693 AC: 25 AN: 3478

EpiCase AF: 0.0483

EpiControl AF: 0.0472

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 11, 2019	This variant is associated with the following publications: (PMID: 28334792) -

Transcobalamin I deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.048
DANN	Benign	0.67
DEOGEN2	Benign	0.021	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.0025	N
LIST_S2	Benign	0.41	T
MetaRNN	Benign	0.0088	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.72	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.98	N
REVEL	Benign	0.015
Sift	Benign	0.60	T
Sift4G	Benign	0.53	T
Polyphen		0.012	B
Vest4		0.035
MPC		0.016
ClinPred		0.0052	T
GERP RS		-8.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.038
gMVP		0.13

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

LitVar

Other links and lift over

dbSNP: rs34528912; hg19: chr11-59631535; COSMIC: COSV57253244; COSMIC: COSV57253244;