3-46443473-G-C

Variant names:

• chr3-46443473-G-C
• rs1042073
• NM_002343.6:c.1623C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_002343.6(LTF):​c.1623C>G​(p.Asn541Lys) 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 1,461,850 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.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: LTF NM_002343.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -5.38
• Publications: 0 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: 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=0.0541839).

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.1623C>G	p.Asn541Lys	missense	Exon 13 of 17	NP_002334.2	P02788-1
	LTF	NM_001321121.2		c.1617C>G	p.Asn539Lys	missense	Exon 13 of 17	NP_001308050.1	E7ER44
	LTF	NM_001321122.2		c.1584C>G	p.Asn528Lys	missense	Exon 16 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.1623C>G	p.Asn541Lys	missense	Exon 13 of 17	ENSP00000231751.4	P02788-1
	LTF	ENST00000417439.5	TSL:1	c.1617C>G	p.Asn539Lys	missense	Exon 13 of 17	ENSP00000405546.1	E7ER44
	LTF	ENST00000947212.1		c.1656C>G	p.Asn552Lys	missense	Exon 14 of 18	ENSP00000617271.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461850 Hom.: 0 Cov.: 40 AF XY: 0.00 AC XY: 0 AN XY: 727230

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111982

Other (OTH) AF: 0.00 AC: 0 AN: 60390

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.0010
DANN	Benign	0.32
DEOGEN2	Benign	0.11	T
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.0068	N
LIST_S2	Benign	0.40	T
M_CAP	Benign	0.0044	T
MetaRNN	Benign	0.054	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.46	N
PhyloP100		-5.4
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-0.42	N
REVEL	Benign	0.012
Sift	Benign	1.0	T
Sift4G	Benign	0.86	T
Polyphen		0.16	B
Vest4		0.091
MutPred		0.39		Gain of methylation at N541 (P = 0.0037)
MVP		0.20
MPC		0.10
ClinPred		0.37	T
GERP RS		-11
Varity_R		0.12
gMVP		0.59
Mutation Taster		=68/32	polymorphism

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

Other links and lift over

dbSNP: rs1042073; hg19: chr3-46484964;