NM_002343.6:c.1737G>C

Variant names:

• chr3-46439467-C-G
• rs2073495
• NM_002343.6:c.1737G>C

Variant summary

Our verdict is Benign. The variant received -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. 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 0.27 (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
• Publications: 45 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=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 rank	MANE	Protein	UniProt
LTF	NM_002343.6	c.1737G>C	p.Glu579Asp	missense_variant	Exon 15 of 17	ENST00000231751.9	NP_002334.2
LTF	NM_001321121.2	c.1731G>C	p.Glu577Asp	missense_variant	Exon 15 of 17		NP_001308050.1
LTF	NM_001321122.2	c.1698G>C	p.Glu566Asp	missense_variant	Exon 18 of 20		NP_001308051.1
LTF	NM_001199149.2	c.1605G>C	p.Glu535Asp	missense_variant	Exon 15 of 17		NP_001186078.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LTF	ENST00000231751.9	c.1737G>C	p.Glu579Asp	missense_variant	Exon 15 of 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

GnomAD2 exomes AF: 0.327 AC: 80411 AN: 245726 AF XY: 0.330

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 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

African (AFR) AF: 0.0863 AC: 2862 AN: 33158

American (AMR) AF: 0.396 AC: 17306 AN: 43742

Ashkenazi Jewish (ASJ) AF: 0.328 AC: 8453 AN: 25792

East Asian (EAS) AF: 0.314 AC: 12428 AN: 39638

South Asian (SAS) AF: 0.331 AC: 28388 AN: 85710

European-Finnish (FIN) AF: 0.274 AC: 14609 AN: 53318

Middle Eastern (MID) AF: 0.381 AC: 2185 AN: 5730

European-Non Finnish (NFE) AF: 0.325 AC: 360040 AN: 1109126

Other (OTH) AF: 0.322 AC: 19357 AN: 60106

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

African (AFR) AF: 0.0979 AC: 4067 AN: 41550

American (AMR) AF: 0.381 AC: 5824 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.339 AC: 1175 AN: 3470

East Asian (EAS) AF: 0.338 AC: 1742 AN: 5160

South Asian (SAS) AF: 0.336 AC: 1623 AN: 4824

European-Finnish (FIN) AF: 0.266 AC: 2820 AN: 10586

Middle Eastern (MID) AF: 0.384 AC: 113 AN: 294

European-Non Finnish (NFE) AF: 0.329 AC: 22392 AN: 67990

Other (OTH) AF: 0.321 AC: 679 AN: 2112

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;.;.;.
PhyloP100		-5.0
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
Mutation Taster		=99/1	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: rs2073495; hg19: chr3-46480958; COSMIC: COSV51606384;