3-46447398-T-C

Position:

• chr3-46447398-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_002343.6(LTF):​c.1213A>G​(p.Lys405Glu) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: LTF NM_002343.6 missense, splice_region
• Scores: Splicing: ADA: 0.6074
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.99

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.39210975).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LTF	NM_002343.6	c.1213A>G	p.Lys405Glu	missense_variant, splice_region_variant	10/17	ENST00000231751.9	NP_002334.2
LTF	NM_001321121.2	c.1207A>G	p.Lys403Glu	missense_variant, splice_region_variant	10/17		NP_001308050.1
LTF	NM_001321122.2	c.1174A>G	p.Lys392Glu	missense_variant, splice_region_variant	13/20		NP_001308051.1
LTF	NM_001199149.2	c.1081A>G	p.Lys361Glu	missense_variant, splice_region_variant	10/17		NP_001186078.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LTF	ENST00000231751.9	c.1213A>G	p.Lys405Glu	missense_variant, splice_region_variant	10/17	1	NM_002343.6	ENSP00000231751	P3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

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

Nov 09, 2021

The c.1213A>G (p.K405E) alteration is located in exon 10 (coding exon 10) of the LTF gene. This alteration results from a A to G substitution at nucleotide position 1213, causing the lysine (K) at amino acid position 405 to be replaced by a glutamic acid (E). 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	0.32
BayesDel_addAF	Benign	-0.096	T
BayesDel_noAF	Benign	-0.38
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T;.;.;.
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.35	T;T;T;T
M_CAP	Benign	0.0063	T
MetaRNN	Benign	0.37	T;T;T;T
MetaSVM	Benign	-1.2	T
MutationAssessor	Benign	1.9	L;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-3.1	D;D;D;D
REVEL	Benign	0.14
Sift	Benign	0.10	T;T;D;T
Sift4G	Benign	0.11	T;T;T;T
Polyphen		0.94	P;.;P;D
Vest4		0.52
MutPred		0.39		Loss of ubiquitination at K405 (P = 0.0127);.;.;.;
MVP		0.33
MPC		0.20
ClinPred		0.98	D
GERP RS		4.8
Varity_R		0.76
gMVP		0.53

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.61
dbscSNV1_RF	Benign	0.60
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-46488889;