3-46443494-A-C

Position:

• chr3-46443494-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002343.6(LTF):​c.1602T>G​(p.Asn534Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: LTF NM_002343.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.416

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12951434).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LTF	NM_002343.6	c.1602T>G	p.Asn534Lys	missense_variant	13/17	ENST00000231751.9	NP_002334.2
LTF	NM_001321121.2	c.1596T>G	p.Asn532Lys	missense_variant	13/17		NP_001308050.1
LTF	NM_001321122.2	c.1563T>G	p.Asn521Lys	missense_variant	16/20		NP_001308051.1
LTF	NM_001199149.2	c.1470T>G	p.Asn490Lys	missense_variant	13/17		NP_001186078.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LTF	ENST00000231751.9	c.1602T>G	p.Asn534Lys	missense_variant	13/17	1	NM_002343.6	ENSP00000231751	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 11, 2023

The c.1602T>G (p.N534K) alteration is located in exon 13 (coding exon 13) of the LTF gene. This alteration results from a T to G substitution at nucleotide position 1602, causing the asparagine (N) at amino acid position 534 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	8.8
DANN	Benign	0.70
DEOGEN2	Benign	0.083	T;.;.;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.18	T;T;T;T
M_CAP	Benign	0.0047	T
MetaRNN	Benign	0.13	T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.5	L;.;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.8	N;N;N;N
REVEL	Benign	0.080
Sift	Benign	0.41	T;T;T;T
Sift4G	Benign	0.47	T;T;T;T
Polyphen		0.011	B;.;B;B
Vest4		0.15
MutPred		0.48		Gain of methylation at N534 (P = 0.007);.;.;.;
MVP		0.21
MPC		0.084
ClinPred		0.19	T
GERP RS		-5.1
Varity_R		0.18
gMVP		0.61

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs1559594139; hg19: chr3-46484985;