3-46439363-G-A

Position:

chr3-46439363-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 1P and 14B. PP3BP4_StrongBP6_ModerateBS1BS2

The ENST00000231751.9(LTF):c.1841C>T(p.Pro614Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00186 in 1,614,156 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0027 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0018 ( 10 hom. )

Consequence

LTF
ENST00000231751.9 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 8.36

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 -13 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 9: AlphaMissense, BayesDel_noAF, Cadd, Dann, Eigen, FATHMM_MKL, MutationAssessor, phyloP100way_vertebrate, PROVEAN [when BayesDel_addAF, max_spliceai, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.019132912).

BP6

Variant 3-46439363-G-A is Benign according to our data. Variant chr3-46439363-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2653732.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00177 (2587/1461852) while in subpopulation MID AF= 0.0187 (108/5768). AF 95% confidence interval is 0.0159. There are 10 homozygotes in gnomad4_exome. There are 1321 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
LTF	NM_002343.6 linkuse as main transcript	c.1841C>T	p.Pro614Leu	missense_variant	15/17	ENST00000231751.9	NP_002334.2
LTF	NM_001321121.2 linkuse as main transcript	c.1835C>T	p.Pro612Leu	missense_variant	15/17		NP_001308050.1
LTF	NM_001321122.2 linkuse as main transcript	c.1802C>T	p.Pro601Leu	missense_variant	18/20		NP_001308051.1
LTF	NM_001199149.2 linkuse as main transcript	c.1709C>T	p.Pro570Leu	missense_variant	15/17		NP_001186078.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LTF	ENST00000231751.9 linkuse as main transcript	c.1841C>T	p.Pro614Leu	missense_variant	15/17	1	NM_002343.6	ENSP00000231751	P3	P02788-1

Frequencies

GnomAD3 genomes

AF:

0.00269

AC:

409

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00779

Gnomad ASJ

AF:

0.0182

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00104

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00144

Gnomad OTH

AF:

0.00621

GnomAD3 exomes

AF:

0.00262

AC:

658

AN:

251336

Hom.:

AF XY:

0.00242

AC XY:

329

AN XY:

135820

show subpopulations

Gnomad AFR exome

AF:

0.00252

Gnomad AMR exome

AF:

0.00474

Gnomad ASJ exome

AF:

0.0166

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.00171

Gnomad NFE exome

AF:

0.00184

Gnomad OTH exome

AF:

0.00587

GnomAD4 exome

AF:

0.00177

AC:

2587

AN:

1461852

Hom.:

Cov.:

AF XY:

0.00182

AC XY:

1321

AN XY:

727230

show subpopulations

Gnomad4 AFR exome

AF:

0.00242

Gnomad4 AMR exome

AF:

0.00487

Gnomad4 ASJ exome

AF:

0.0179

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000185

Gnomad4 FIN exome

AF:

0.00172

Gnomad4 NFE exome

AF:

0.00123

Gnomad4 OTH exome

AF:

0.00379

GnomAD4 genome

AF:

0.00268

AC:

408

AN:

152304

Hom.:

Cov.:

AF XY:

0.00265

AC XY:

197

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.00238

Gnomad4 AMR

AF:

0.00778

Gnomad4 ASJ

AF:

0.0182

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00104

Gnomad4 NFE

AF:

0.00144

Gnomad4 OTH

AF:

0.00615

Alfa

AF:

0.00263

Hom.:

Bravo

AF:

0.00320

TwinsUK

AF:

0.00216

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.00233

AC:

ExAC

AF:

0.00250

AC:

303

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00245

EpiControl

AF:

0.00237

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jan 01, 2023

LTF: BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.58

BayesDel_addAF

Benign

-0.045

BayesDel_noAF

Pathogenic

0.16

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.30

T;.;.;.

Eigen

Pathogenic

0.82

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.97

D;D;D;D

M_CAP

Uncertain

0.087

MetaRNN

Benign

0.019

T;T;T;T

MetaSVM

Benign

-0.44

MutationAssessor

Pathogenic

4.0

H;.;.;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.54

PROVEAN

Pathogenic

-8.7

D;D;D;D

REVEL

Uncertain

0.58

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Uncertain

0.0020

D;D;D;D

Polyphen

1.0

D;.;D;D

Vest4

0.65

MVP

0.65

MPC

0.42

ClinPred

0.15

GERP RS

5.1

Varity_R

0.94

gMVP

0.90

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