3-46439467-C-G

Position:

• chr3-46439467-C-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002343.6(LTF):​c.1737G>C​(p.Glu579Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.315 in 1,608,494 control chromosomes in the GnomAD database, including 82,871 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.27 (6407 hom., cov: 33)
  • Exomes 𝑓: 0.32 (76464 hom.)
• Consequence: LTF NM_002343.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -5.03

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]

LTF (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0013298988).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.373 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LTF	NM_002343.6	c.1737G>C	p.Glu579Asp	missense_variant	15/17	ENST00000231751.9	NP_002334.2
LTF	NM_001321121.2	c.1731G>C	p.Glu577Asp	missense_variant	15/17		NP_001308050.1
LTF	NM_001321122.2	c.1698G>C	p.Glu566Asp	missense_variant	18/20		NP_001308051.1
LTF	NM_001199149.2	c.1605G>C	p.Glu535Asp	missense_variant	15/17		NP_001186078.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LTF	ENST00000231751.9	c.1737G>C	p.Glu579Asp	missense_variant	15/17	1	NM_002343.6	ENSP00000231751.4

Frequencies

GnomAD3 genomes AF: 0.267 AC: 40664 AN: 152056 Hom.: 6410 Cov.: 33

Gnomad AFR AF: 0.0980

Gnomad AMI AF: 0.234

Gnomad AMR AF: 0.381

Gnomad ASJ AF: 0.339

Gnomad EAS AF: 0.338

Gnomad SAS AF: 0.338

Gnomad FIN AF: 0.266

Gnomad MID AF: 0.377

Gnomad NFE AF: 0.329

Gnomad OTH AF: 0.325

GnomAD3 exomes AF: 0.327 AC: 80411 AN: 245726 Hom.: 13689 AF XY: 0.330 AC XY: 43890 AN XY: 132870

Gnomad AFR exome AF: 0.0934

Gnomad AMR exome AF: 0.406

Gnomad ASJ exome AF: 0.337

Gnomad EAS exome AF: 0.355

Gnomad SAS exome AF: 0.337

Gnomad FIN exome AF: 0.275

Gnomad NFE exome AF: 0.339

Gnomad OTH exome AF: 0.351

GnomAD4 exome AF: 0.320 AC: 465628 AN: 1456320 Hom.: 76464 Cov.: 38 AF XY: 0.321 AC XY: 232352 AN XY: 724232

Gnomad4 AFR exome AF: 0.0863

Gnomad4 AMR exome AF: 0.396

Gnomad4 ASJ exome AF: 0.328

Gnomad4 EAS exome AF: 0.314

Gnomad4 SAS exome AF: 0.331

Gnomad4 FIN exome AF: 0.274

Gnomad4 NFE exome AF: 0.325

Gnomad4 OTH exome AF: 0.322

GnomAD4 genome AF: 0.267 AC: 40648 AN: 152174 Hom.: 6407 Cov.: 33 AF XY: 0.270 AC XY: 20093 AN XY: 74388

Gnomad4 AFR AF: 0.0979

Gnomad4 AMR AF: 0.381

Gnomad4 ASJ AF: 0.339

Gnomad4 EAS AF: 0.338

Gnomad4 SAS AF: 0.336

Gnomad4 FIN AF: 0.266

Gnomad4 NFE AF: 0.329

Gnomad4 OTH AF: 0.321

Alfa AF: 0.303 Hom.: 4411

Bravo AF: 0.265

TwinsUK AF: 0.338 AC: 1255

ALSPAC AF: 0.329 AC: 1268

ESP6500AA AF: 0.100 AC: 441

ESP6500EA AF: 0.339 AC: 2912

ExAC AF: 0.319 AC: 38745

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.80	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.0030
DANN	Benign	0.43
DEOGEN2	Benign	0.086	T;.;.;.
Eigen	Benign	-1.9
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.015	N
LIST_S2	Benign	0.055	T;T;T;T
MetaRNN	Benign	0.0013	T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.4	L;.;.;.
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.4	N;N;N;N
REVEL	Benign	0.015
Sift	Benign	0.48	T;T;T;T
Sift4G	Benign	0.48	T;T;T;T
Polyphen		0.0	B;.;B;B
Vest4		0.029
MPC		0.064
ClinPred		0.018	T
GERP RS		-10
Varity_R		0.22
gMVP		0.66

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

Publications

LitVar

Other links and lift over

dbSNP: rs2073495; hg19: chr3-46480958; COSMIC: COSV51606384;