rs1126477

Positions:

• chr3-46459778-C-T

Variant summary

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

The NM_002343.6(LTF):​c.85G>A​(p.Ala29Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.284 in 1,539,356 control chromosomes in the GnomAD database, including 70,124 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 0.53 (14860 hom., cov: 30)
  • Exomes 𝑓: 0.26 (55264 hom.)
• Consequence: LTF NM_002343.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.85

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

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.1497925E-6).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.74 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LTF	NM_002343.6	c.85G>A	p.Ala29Thr	missense_variant	2/17	ENST00000231751.9	NP_002334.2
LTF	NM_001321121.2	c.85G>A	p.Ala29Thr	missense_variant	2/17		NP_001308050.1
LTF	NM_001321122.2	c.46G>A	p.Ala16Thr	missense_variant	5/20		NP_001308051.1
LTF	NM_001199149.2	c.-48G>A		5_prime_UTR_variant	2/17		NP_001186078.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LTF	ENST00000231751.9	c.85G>A	p.Ala29Thr	missense_variant	2/17	1	NM_002343.6	ENSP00000231751	P3

Frequencies

GnomAD3 genomes AF: 0.530 AC: 60032 AN: 113372 Hom.: 14825 Cov.: 30

Gnomad AFR AF: 0.747

Gnomad AMI AF: 0.347

Gnomad AMR AF: 0.545

Gnomad ASJ AF: 0.450

Gnomad EAS AF: 0.561

Gnomad SAS AF: 0.543

Gnomad FIN AF: 0.407

Gnomad MID AF: 0.500

Gnomad NFE AF: 0.361

Gnomad OTH AF: 0.511

GnomAD3 exomes AF: 0.344 AC: 67494 AN: 196136 Hom.: 11887 AF XY: 0.332 AC XY: 35619 AN XY: 107406

Gnomad AFR exome AF: 0.718

Gnomad AMR exome AF: 0.417

Gnomad ASJ exome AF: 0.366

Gnomad EAS exome AF: 0.469

Gnomad SAS exome AF: 0.402

Gnomad FIN exome AF: 0.267

Gnomad NFE exome AF: 0.259

Gnomad OTH exome AF: 0.330

GnomAD4 exome AF: 0.265 AC: 377272 AN: 1425858 Hom.: 55264 Cov.: 34 AF XY: 0.266 AC XY: 188388 AN XY: 708678

Gnomad4 AFR exome AF: 0.717

Gnomad4 AMR exome AF: 0.366

Gnomad4 ASJ exome AF: 0.331

Gnomad4 EAS exome AF: 0.420

Gnomad4 SAS exome AF: 0.364

Gnomad4 FIN exome AF: 0.254

Gnomad4 NFE exome AF: 0.233

Gnomad4 OTH exome AF: 0.302

GnomAD4 genome AF: 0.530 AC: 60125 AN: 113498 Hom.: 14860 Cov.: 30 AF XY: 0.534 AC XY: 29421 AN XY: 55136

Gnomad4 AFR AF: 0.747

Gnomad4 AMR AF: 0.546

Gnomad4 ASJ AF: 0.450

Gnomad4 EAS AF: 0.561

Gnomad4 SAS AF: 0.544

Gnomad4 FIN AF: 0.407

Gnomad4 NFE AF: 0.361

Gnomad4 OTH AF: 0.518

Alfa AF: 0.279 Hom.: 14110

Bravo AF: 0.419

TwinsUK AF: 0.230 AC: 852

ALSPAC AF: 0.240 AC: 924

ESP6500AA AF: 0.696 AC: 3066

ESP6500EA AF: 0.244 AC: 2095

ExAC AF: 0.328 AC: 39800

Asia WGS AF: 0.448 AC: 1554 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.78	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	0.011
DANN	Benign	0.14
DEOGEN2	Benign	0.042	T;.;.;.
Eigen	Benign	-2.3
Eigen_PC	Benign	-2.3
FATHMM_MKL	Benign	0.0014	N
LIST_S2	Benign	0.52	T;T;T;T
MetaRNN	Benign	0.0000011	T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.85	N;.;.;.
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.32	T
PROVEAN	Benign	1.8	N;N;N;N
REVEL	Benign	0.018
Sift	Benign	1.0	T;T;T;T
Sift4G	Benign	1.0	T;T;T;T
Polyphen		0.0040	B;B;B;.
Vest4		0.031
MPC		1.6
ClinPred		0.0019	T
GERP RS		-3.6
Varity_R		0.098
gMVP		0.58

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1126477; hg19: chr3-46501268; COSMIC: COSV51606899; COSMIC: COSV51606899;