NM_002343.6:c.1444G>T

Variant names:

• chr3-46445350-C-A
• rs147094293
• NM_002343.6:c.1444G>T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_002343.6(LTF):​c.1444G>T​(p.Val482Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0014 in 1,613,862 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0026 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (0 hom.)
• Consequence: LTF NM_002343.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0840

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009766728).
• BP6: Variant 3-46445350-C-A is Benign according to our data. Variant chr3-46445350-C-A is described in ClinVar as [Benign]. Clinvar id is 721972.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LTF	NM_002343.6	c.1444G>T	p.Val482Leu	missense_variant	Exon 12 of 17	ENST00000231751.9	NP_002334.2
LTF	NM_001321121.2	c.1438G>T	p.Val480Leu	missense_variant	Exon 12 of 17		NP_001308050.1
LTF	NM_001321122.2	c.1405G>T	p.Val469Leu	missense_variant	Exon 15 of 20		NP_001308051.1
LTF	NM_001199149.2	c.1312G>T	p.Val438Leu	missense_variant	Exon 12 of 17		NP_001186078.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LTF	ENST00000231751.9	c.1444G>T	p.Val482Leu	missense_variant	Exon 12 of 17	1	NM_002343.6	ENSP00000231751.4

Frequencies

GnomAD3 genomes AF: 0.00258 AC: 393 AN: 152232 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00615

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000941

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000988 AC: 248 AN: 251076 Hom.: 0 AF XY: 0.000862 AC XY: 117 AN XY: 135720

Gnomad AFR exome AF: 0.00634

Gnomad AMR exome AF: 0.00116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000863

Gnomad OTH exome AF: 0.00115

GnomAD4 exome AF: 0.00127 AC: 1862 AN: 1461512 Hom.: 0 Cov.: 31 AF XY: 0.00122 AC XY: 888 AN XY: 727084

Gnomad4 AFR exome AF: 0.00514

Gnomad4 AMR exome AF: 0.00125

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.00136

Gnomad4 OTH exome AF: 0.00190

GnomAD4 genome AF: 0.00261 AC: 397 AN: 152350 Hom.: 2 Cov.: 32 AF XY: 0.00254 AC XY: 189 AN XY: 74500

Gnomad4 AFR AF: 0.00623

Gnomad4 AMR AF: 0.00457

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000941

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000926 Hom.: 0

Bravo AF: 0.00305

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00590 AC: 26

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.000980 AC: 119

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00131

EpiControl AF: 0.00101

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 27, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.21	T;.;.;.
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.80	T;T;T;T
M_CAP	Benign	0.0081	T
MetaRNN	Benign	0.0098	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L;.;.;.
PrimateAI	Benign	0.31	T
PROVEAN	Uncertain	-2.4	N;N;N;N
REVEL	Benign	0.052
Sift	Benign	0.32	T;T;T;T
Sift4G	Benign	0.31	T;T;T;T
Polyphen		0.30	B;.;B;B
Vest4		0.23
MutPred		0.63		Gain of glycosylation at T480 (P = 0.0289);.;.;.;
MVP		0.40
MPC		0.093
ClinPred		0.058	T
GERP RS		2.2
Varity_R		0.35
gMVP		0.59

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: rs147094293; hg19: chr3-46486841;