3-46459794-C-CCTT

Variant names:

• chr3-46459794-C-CCTT
• rs10662431
• NM_002343.6:c.68_69insAAG

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 1P and 8B. PM4_Supporting BA1

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.27
• Publications: 21 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 -7 ACMG points.

• 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	c.68_69insAAG	p.Arg23dup	disruptive_inframe_insertion	Exon 2 of 17	ENST00000231751.9	NP_002334.2
LTF	NM_001321121.2	c.68_69insAAG	p.Arg23dup	disruptive_inframe_insertion	Exon 2 of 17		NP_001308050.1
LTF	NM_001321122.2	c.29_30insAAG	p.Arg10dup	disruptive_inframe_insertion	Exon 5 of 20		NP_001308051.1
LTF	NM_001199149.2	c.-65_-64insAAG		5_prime_UTR_variant	Exon 2 of 17		NP_001186078.1

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.981 AC: 149178 AN: 151990 Hom.: 73219 Cov.: 0

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

GnomAD2 exomes AF: 0.981 AC: 202502 AN: 206520 AF XY: 0.981

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 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.: 36 AF XY: 0.971 AC XY: 681565 AN XY: 701606

African (AFR) AF: 0.996 AC: 28900 AN: 29030

American (AMR) AF: 0.986 AC: 35072 AN: 35554

Ashkenazi Jewish (ASJ) AF: 0.988 AC: 24653 AN: 24954

East Asian (EAS) AF: 1.00 AC: 34660 AN: 34662

South Asian (SAS) AF: 0.992 AC: 77949 AN: 78566

European-Finnish (FIN) AF: 0.982 AC: 51960 AN: 52914

Middle Eastern (MID) AF: 0.993 AC: 5277 AN: 5312

European-Non Finnish (NFE) AF: 0.966 AC: 1055268 AN: 1092890

Other (OTH) AF: 0.974 AC: 56722 AN: 58238

GnomAD4 genome AF: 0.981 AC: 149293 AN: 152108 Hom.: 73275 Cov.: 0 AF XY: 0.983 AC XY: 73074 AN XY: 74352

African (AFR) AF: 0.994 AC: 41230 AN: 41478

American (AMR) AF: 0.986 AC: 15075 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.989 AC: 3434 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5160 AN: 5162

South Asian (SAS) AF: 0.993 AC: 4776 AN: 4810

European-Finnish (FIN) AF: 0.984 AC: 10412 AN: 10582

Middle Eastern (MID) AF: 0.997 AC: 293 AN: 294

European-Non Finnish (NFE) AF: 0.970 AC: 65931 AN: 67994

Other (OTH) AF: 0.982 AC: 2074 AN: 2112

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
PhyloP100		-1.3
Mutation Taster		=89/11	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs10662431; hg19: chr3-46501284; COSMIC: COSV51606348; COSMIC: COSV51606348;