chr3-46439310-A-T

Variant names:

• chr3-46439310-A-T
• rs9110
• NM_002343.6:c.1894T>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_002343.6(LTF):​c.1894T>A​(p.Leu632Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,782 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: LTF NM_002343.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.62
• Publications: 25 publications found

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

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.871

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002343.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LTF	NM_002343.6	MANE Select	c.1894T>A	p.Leu632Met	missense	Exon 15 of 17	NP_002334.2	P02788-1
	LTF	NM_001321121.2		c.1888T>A	p.Leu630Met	missense	Exon 15 of 17	NP_001308050.1	E7ER44
	LTF	NM_001321122.2		c.1855T>A	p.Leu619Met	missense	Exon 18 of 20	NP_001308051.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LTF	ENST00000231751.9	TSL:1 MANE Select	c.1894T>A	p.Leu632Met	missense	Exon 15 of 17	ENSP00000231751.4	P02788-1
	LTF	ENST00000417439.5	TSL:1	c.1888T>A	p.Leu630Met	missense	Exon 15 of 17	ENSP00000405546.1	E7ER44
	LTF	ENST00000947212.1		c.1927T>A	p.Leu643Met	missense	Exon 16 of 18	ENSP00000617271.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459782 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 726200

African (AFR) AF: 0.00 AC: 0 AN: 33386

American (AMR) AF: 0.00 AC: 0 AN: 44362

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25942

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86014

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53376

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110968

Other (OTH) AF: 0.00 AC: 0 AN: 60296

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.060	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.27	T
Eigen	Uncertain	0.30
Eigen_PC	Benign	0.12
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.045	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		1.6
PrimateAI	Uncertain	0.48	T
PROVEAN	Benign	-1.7	N
REVEL	Uncertain	0.37
Sift	Uncertain	0.024	D
Sift4G	Uncertain	0.023	D
Polyphen		1.0	D
Vest4		0.24
MutPred		0.81		Gain of disorder (P = 0.0633)
MVP		0.47
MPC		0.37
ClinPred		0.97	D
GERP RS		5.1
Varity_R		0.58
gMVP		0.67
Mutation Taster		=65/35	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.39		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.39		Position offset: 4

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs9110; hg19: chr3-46480801;