3-46459794-C-CCTT

Variant names:

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

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 3P and 8B. PM1 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

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 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	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

GnomAD3 exomes AF: 0.981 AC: 202502 AN: 206520 Hom.: 99297 AF XY: 0.981 AC XY: 110789 AN XY: 112980

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

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.: 0 AF XY: 0.983 AC XY: 73074 AN XY: 74352

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

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs10662431; hg19: chr3-46501284;