Genetic Variant NM_002343.6:c.68_69insAAG (chr3-46459794-C-CCTT) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 3P and 8B. PM1PM4_SupportingBA1

The NM_002343.6(LTF):c.68_69insAAG(p.Arg23dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.972 in 1,564,228 control chromosomes in the GnomAD database, including 738,447 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.98 ( 73275 hom., cov: 0)

Exomes 𝑓: 0.97 ( 665172 hom. )

Consequence

LTF
NM_002343.6 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.27

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

PM1

In a site Interaction with PspA (size 0) in uniprot entity TRFL_HUMAN

PM4

Nonframeshift variant in NON repetitive region in NM_002343.6. Strenght limited to Supporting due to length of the change: 1aa.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.986 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LTF	NM_002343.6 link	c.68_69insAAG	p.Arg23dup	disruptive_inframe_insertion	Exon 2 of 17	ENST00000231751.9	NP_002334.2	P02788-1V9HWI4
LTF	NM_001321121.2 link	c.68_69insAAG	p.Arg23dup	disruptive_inframe_insertion	Exon 2 of 17		NP_001308050.1	P02788Q2TUW9V9HWI4E7ER44
LTF	NM_001321122.2 link	c.29_30insAAG	p.Arg10dup	disruptive_inframe_insertion	Exon 5 of 20		NP_001308051.1	P02788V9HWI4B3KSL2
LTF	NM_001199149.2 link	c.-65_-64insAAG		5_prime_UTR_variant	Exon 2 of 17		NP_001186078.1	P02788-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LTF	ENST00000231751.9 link	c.68_69insAAG	p.Arg23dup	disruptive_inframe_insertion	Exon 2 of 17	1	NM_002343.6	ENSP00000231751.4		P02788-1

Frequencies

GnomAD3 genomes

AF:

0.981

AC:

149178

AN:

151990

Hom.:

73219

Cov.:

show subpopulations

Gnomad AFR

AF:

0.994

Gnomad AMI

AF:

0.998

Gnomad AMR

AF:

0.986

Gnomad ASJ

AF:

0.989

Gnomad EAS

AF:

1.00

Gnomad SAS

AF:

0.993

Gnomad FIN

AF:

0.984

Gnomad MID

AF:

0.997

Gnomad NFE

AF:

0.970

Gnomad OTH

AF:

0.982

GnomAD3 exomes

AF:

0.981

AC:

202502

AN:

206520

Hom.:

99297

AF XY:

0.981

AC XY:

110789

AN XY:

112980

show subpopulations

Gnomad AFR exome

AF:

0.994

Gnomad AMR exome

AF:

0.986

Gnomad ASJ exome

AF:

0.989

Gnomad EAS exome

AF:

1.00

Gnomad SAS exome

AF:

0.993

Gnomad FIN exome

AF:

0.983

Gnomad NFE exome

AF:

0.971

Gnomad OTH exome

AF:

0.979

GnomAD4 exome

AF:

0.970

AC:

1370461

AN:

1412120

Hom.:

665172

Cov.:

AF XY:

0.971

AC XY:

681565

AN XY:

701606

show subpopulations

Gnomad4 AFR exome

AF:

0.996

Gnomad4 AMR exome

AF:

0.986

Gnomad4 ASJ exome

AF:

0.988

Gnomad4 EAS exome

AF:

1.00

Gnomad4 SAS exome

AF:

0.992

Gnomad4 FIN exome

AF:

0.982

Gnomad4 NFE exome

AF:

0.966

Gnomad4 OTH exome

AF:

0.974

GnomAD4 genome

AF:

0.981

AC:

149293

AN:

152108

Hom.:

73275

Cov.:

AF XY:

0.983

AC XY:

73074

AN XY:

74352

show subpopulations

Gnomad4 AFR

AF:

0.994

Gnomad4 AMR

AF:

0.986

Gnomad4 ASJ

AF:

0.989

Gnomad4 EAS

AF:

1.00

Gnomad4 SAS

AF:

0.993

Gnomad4 FIN

AF:

0.984

Gnomad4 NFE

AF:

0.970

Gnomad4 OTH

AF:

0.982

Alfa

AF:

0.971

Hom.:

14936

Asia WGS

AF:

0.996

AC:

3465

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over