3-46446446-C-T

Position:

chr3-46446446-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_002343.6(LTF):c.1351G>A(p.Val451Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00751 in 1,612,990 control chromosomes in the GnomAD database, including 82 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0050 ( 5 hom., cov: 32)

Exomes 𝑓: 0.0078 ( 77 hom. )

Consequence

LTF
NM_002343.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -1.82

Variant links:

Genes affected

LTF (HGNC:6720): (lactotransferrin) This gene is a member of the transferrin family of genes and its protein product is found in the secondary granules of neutrophils. The protein is a major iron-binding protein in milk and body secretions with an antimicrobial activity, making it an important component of the non-specific immune system. The protein demonstrates a broad spectrum of properties, including regulation of iron homeostasis, host defense against a broad range of microbial infections, anti-inflammatory activity, regulation of cellular growth and differentiation and protection against cancer development and metastasis. Antimicrobial, antiviral, antifungal and antiparasitic activity has been found for this protein and its peptides. Activity against both DNA and RNA viruses has been found, including activity against SARS-CoV-2, and HIV. [provided by RefSeq, Jul 2021]

LTF links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0039860904).

BP6

Variant 3-46446446-C-T is Benign according to our data. Variant chr3-46446446-C-T is described in ClinVar as [Benign]. Clinvar id is 785795.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00777 (11354/1460666) while in subpopulation MID AF= 0.0253 (146/5764). AF 95% confidence interval is 0.022. There are 77 homozygotes in gnomad4_exome. There are 6090 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 5 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
LTF	NM_002343.6 linkuse as main transcript	c.1351G>A	p.Val451Met	missense_variant	11/17	ENST00000231751.9	NP_002334.2
LTF	NM_001321121.2 linkuse as main transcript	c.1345G>A	p.Val449Met	missense_variant	11/17		NP_001308050.1
LTF	NM_001321122.2 linkuse as main transcript	c.1312G>A	p.Val438Met	missense_variant	14/20		NP_001308051.1
LTF	NM_001199149.2 linkuse as main transcript	c.1219G>A	p.Val407Met	missense_variant	11/17		NP_001186078.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LTF	ENST00000231751.9 linkuse as main transcript	c.1351G>A	p.Val451Met	missense_variant	11/17	1	NM_002343.6	ENSP00000231751	P3	P02788-1

Frequencies

GnomAD3 genomes

AF:

0.00502

AC:

764

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00128

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00393

Gnomad ASJ

AF:

0.0190

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.0170

Gnomad FIN

AF:

0.000660

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.00681

Gnomad OTH

AF:

0.0105

GnomAD3 exomes

AF:

0.00804

AC:

2015

AN:

250556

Hom.:

AF XY:

0.00909

AC XY:

1231

AN XY:

135424

show subpopulations

Gnomad AFR exome

AF:

0.00148

Gnomad AMR exome

AF:

0.00502

Gnomad ASJ exome

AF:

0.0186

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0215

Gnomad FIN exome

AF:

0.000508

Gnomad NFE exome

AF:

0.00796

Gnomad OTH exome

AF:

0.0105

GnomAD4 exome

AF:

0.00777

AC:

11354

AN:

1460666

Hom.:

Cov.:

AF XY:

0.00838

AC XY:

6090

AN XY:

726612

show subpopulations

Gnomad4 AFR exome

AF:

0.000927

Gnomad4 AMR exome

AF:

0.00509

Gnomad4 ASJ exome

AF:

0.0172

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.0221

Gnomad4 FIN exome

AF:

0.000655

Gnomad4 NFE exome

AF:

0.00724

Gnomad4 OTH exome

AF:

0.00850

GnomAD4 genome

AF:

0.00502

AC:

765

AN:

152324

Hom.:

Cov.:

AF XY:

0.00475

AC XY:

354

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.00127

Gnomad4 AMR

AF:

0.00392

Gnomad4 ASJ

AF:

0.0190

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0174

Gnomad4 FIN

AF:

0.000660

Gnomad4 NFE

AF:

0.00681

Gnomad4 OTH

AF:

0.0104

Alfa

AF:

0.00759

Hom.:

Bravo

AF:

0.00495

TwinsUK

AF:

0.00620

AC:

ALSPAC

AF:

0.00856

AC:

ESP6500AA

AF:

0.00204

AC:

ESP6500EA

AF:

0.00978

AC:

ExAC

AF:

0.00844

AC:

1025

Asia WGS

AF:

0.0100

AC:

AN:

3478

EpiCase

AF:

0.00967

EpiControl

AF:

0.0101

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 31, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.69

CADD

Benign

4.0

DANN

Uncertain

0.98

DEOGEN2

Benign

0.084

T;.;.;.

Eigen

Benign

-0.70

Eigen_PC

Benign

-0.89

FATHMM_MKL

Benign

0.0074

LIST_S2

Benign

0.15

T;T;T;T

MetaRNN

Benign

0.0040

T;T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.7

L;.;.;.

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.78

N;N;N;N

REVEL

Benign

0.083

Sift

Benign

0.034

D;D;D;D

Sift4G

Benign

0.13

T;T;T;T

Polyphen

0.79

P;.;P;D

Vest4

0.17

MVP

0.13

MPC

0.12

ClinPred

0.016

GERP RS

-5.3

Varity_R

0.15

gMVP

0.35

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over