Genetic Variant LTF:p.Met622Thr (chr3-46439339-A-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_002343.6(LTF):c.1865T>C(p.Met622Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,834 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M622R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

LTF
NM_002343.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.60

Publications

0 publications found

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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.030159324).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LTF	NM_002343.6 link	c.1865T>C	p.Met622Thr	missense_variant	Exon 15 of 17	ENST00000231751.9	NP_002334.2	P02788-1V9HWI4
LTF	NM_001321121.2 link	c.1859T>C	p.Met620Thr	missense_variant	Exon 15 of 17		NP_001308050.1	P02788Q2TUW9V9HWI4E7ER44
LTF	NM_001321122.2 link	c.1826T>C	p.Met609Thr	missense_variant	Exon 18 of 20		NP_001308051.1	P02788V9HWI4B3KSL2
LTF	NM_001199149.2 link	c.1733T>C	p.Met578Thr	missense_variant	Exon 15 of 17		NP_001186078.1	P02788-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LTF	ENST00000231751.9 link	c.1865T>C	p.Met622Thr	missense_variant	Exon 15 of 17	1	NM_002343.6	ENSP00000231751.4		P02788-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461834

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727210

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33474

American (AMR)

AF:

0.00

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111980

Other (OTH)

AF:

0.00

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.049

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.86

CADD

Benign

0.0010

(source)

DANN

Benign

0.21

DEOGEN2

Benign

0.044

T;.;.;.

Eigen

Benign

-2.8

Eigen_PC

Benign

-2.8

FATHMM_MKL

Benign

0.0030

LIST_S2

Benign

0.0052

T;T;T;T

M_CAP

Benign

0.0027

MetaRNN

Benign

0.030

T;T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

-0.13

N;.;.;.

PhyloP100

-2.6

PrimateAI

Benign

0.28

PROVEAN

Benign

0.26

N;N;N;N

REVEL

Benign

0.012

Sift

Benign

0.14

T;T;T;T

Sift4G

Benign

0.087

T;T;T;T

Polyphen

0.0

B;.;B;B

Vest4

0.047

MutPred

0.45

Loss of stability (P = 0.0171);.;.;.;

MVP

0.055

MPC

0.078

ClinPred

0.074

GERP RS

-10

Varity_R

0.089

gMVP

0.39

Mutation Taster

=94/6

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over