3-46459723-T-C

Variant names:

• chr3-46459723-T-C
• rs1126478
• NM_002343.6:c.140A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002343.6(LTF):​c.140A>G​(p.Lys47Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.369 in 1,575,478 control chromosomes in the GnomAD database, including 122,098 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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: 𝑓 0.51 (23912 hom., cov: 31)
  • Exomes 𝑓: 0.35 (98186 hom.)
• Consequence: LTF NM_002343.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.40
• Publications: 80 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=8.6380334E-7).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.859 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LTF	NM_002343.6	c.140A>G	p.Lys47Arg	missense_variant	Exon 2 of 17	ENST00000231751.9	NP_002334.2
LTF	NM_001321121.2	c.140A>G	p.Lys47Arg	missense_variant	Exon 2 of 17		NP_001308050.1
LTF	NM_001321122.2	c.101A>G	p.Lys34Arg	missense_variant	Exon 5 of 20		NP_001308051.1
LTF	NM_001199149.2	c.8A>G	p.Lys3Arg	missense_variant	Exon 2 of 17		NP_001186078.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LTF	ENST00000231751.9	c.140A>G	p.Lys47Arg	missense_variant	Exon 2 of 17	1	NM_002343.6	ENSP00000231751.4

Frequencies

GnomAD3 genomes AF: 0.508 AC: 77114 AN: 151736 Hom.: 23848 Cov.: 31

Gnomad AFR AF: 0.866

Gnomad AMI AF: 0.326

Gnomad AMR AF: 0.453

Gnomad ASJ AF: 0.371

Gnomad EAS AF: 0.680

Gnomad SAS AF: 0.539

Gnomad FIN AF: 0.400

Gnomad MID AF: 0.474

Gnomad NFE AF: 0.316

Gnomad OTH AF: 0.456

GnomAD2 exomes AF: 0.411 AC: 89929 AN: 218734 AF XY: 0.404

Gnomad AFR exome AF: 0.871

Gnomad AMR exome AF: 0.405

Gnomad ASJ exome AF: 0.367

Gnomad EAS exome AF: 0.668

Gnomad FIN exome AF: 0.395

Gnomad NFE exome AF: 0.306

Gnomad OTH exome AF: 0.371

GnomAD4 exome AF: 0.354 AC: 503563 AN: 1423624 Hom.: 98186 Cov.: 35 AF XY: 0.357 AC XY: 252355 AN XY: 707444

African (AFR) AF: 0.892 AC: 26965 AN: 30246

American (AMR) AF: 0.415 AC: 16248 AN: 39126

Ashkenazi Jewish (ASJ) AF: 0.368 AC: 9315 AN: 25344

East Asian (EAS) AF: 0.658 AC: 23076 AN: 35090

South Asian (SAS) AF: 0.518 AC: 41551 AN: 80284

European-Finnish (FIN) AF: 0.401 AC: 21248 AN: 53020

Middle Eastern (MID) AF: 0.444 AC: 2513 AN: 5656

European-Non Finnish (NFE) AF: 0.309 AC: 339216 AN: 1096036

Other (OTH) AF: 0.398 AC: 23431 AN: 58822

GnomAD4 genome AF: 0.509 AC: 77244 AN: 151854 Hom.: 23912 Cov.: 31 AF XY: 0.514 AC XY: 38123 AN XY: 74194

African (AFR) AF: 0.866 AC: 35892 AN: 41438

American (AMR) AF: 0.453 AC: 6914 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.371 AC: 1286 AN: 3466

East Asian (EAS) AF: 0.678 AC: 3502 AN: 5162

South Asian (SAS) AF: 0.540 AC: 2589 AN: 4796

European-Finnish (FIN) AF: 0.400 AC: 4208 AN: 10524

Middle Eastern (MID) AF: 0.476 AC: 138 AN: 290

European-Non Finnish (NFE) AF: 0.316 AC: 21446 AN: 67908

Other (OTH) AF: 0.462 AC: 972 AN: 2106

Alfa AF: 0.381 Hom.: 47694

Bravo AF: 0.525

TwinsUK AF: 0.308 AC: 1141

ALSPAC AF: 0.318 AC: 1227

ESP6500AA AF: 0.859 AC: 3783

ESP6500EA AF: 0.316 AC: 2720

ExAC AF: 0.436 AC: 52909

Asia WGS AF: 0.617 AC: 2145 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	0.0060
DANN	Benign	0.73
DEOGEN2	Benign	0.071	T;.;.;.;.
Eigen	Benign	-2.1
Eigen_PC	Benign	-2.2
FATHMM_MKL	Benign	0.0086	N
LIST_S2	Benign	0.12	T;T;T;T;T
MetaRNN	Benign	8.6e-7	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.32	N;.;.;.;.
PhyloP100		-2.4
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.97	N;N;N;N;N
REVEL	Benign	0.016
Sift	Benign	0.40	T;T;T;T;T
Sift4G	Benign	0.41	T;T;T;T;T
Polyphen		0.0	B;.;B;B;.
Vest4		0.025
MPC		0.058
ClinPred		0.029	T
GERP RS		-9.7
Varity_R		0.092
gMVP		0.52
Mutation Taster		=98/2	polymorphism (auto)

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: rs1126478; hg19: chr3-46501213; COSMIC: COSV51606197; COSMIC: COSV51606197;