chr3-46438095-T-C

Variant names:

• chr3-46438095-T-C
• rs200727604
• NM_002343.6:c.1943A>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_002343.6(LTF):​c.1943A>G​(p.Asp648Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00019 in 1,614,040 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00019 (4 hom.)
• Consequence: LTF NM_002343.6 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0720
• Publications: 3 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01523155).
• BP6: Variant 3-46438095-T-C is Benign according to our data. Variant chr3-46438095-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 2236774.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome4 at 4 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002343.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LTF	NM_002343.6	MANE Select	c.1943A>G	p.Asp648Gly	missense	Exon 16 of 17	NP_002334.2	P02788-1
	LTF	NM_001321121.2		c.1937A>G	p.Asp646Gly	missense	Exon 16 of 17	NP_001308050.1	E7ER44
	LTF	NM_001321122.2		c.1904A>G	p.Asp635Gly	missense	Exon 19 of 20	NP_001308051.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LTF	ENST00000231751.9	TSL:1 MANE Select	c.1943A>G	p.Asp648Gly	missense	Exon 16 of 17	ENSP00000231751.4	P02788-1
	LTF	ENST00000417439.5	TSL:1	c.1937A>G	p.Asp646Gly	missense	Exon 16 of 17	ENSP00000405546.1	E7ER44
	LTF	ENST00000947212.1		c.1976A>G	p.Asp659Gly	missense	Exon 17 of 18	ENSP00000617271.1

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 22 AN: 152226 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000183 AC: 46 AN: 251122 AF XY: 0.000177

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000465

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000185

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000194 AC: 284 AN: 1461696 Hom.: 4 Cov.: 31 AF XY: 0.000180 AC XY: 131 AN XY: 727160

African (AFR) AF: 0.0000897 AC: 3 AN: 33460

American (AMR) AF: 0.000291 AC: 13 AN: 44656

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.000128 AC: 11 AN: 86232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.0116 AC: 67 AN: 5766

European-Non Finnish (NFE) AF: 0.000153 AC: 170 AN: 1111958

Other (OTH) AF: 0.000331 AC: 20 AN: 60384

GnomAD4 genome AF: 0.000151 AC: 23 AN: 152344 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74506

African (AFR) AF: 0.0000962 AC: 4 AN: 41570

American (AMR) AF: 0.000131 AC: 2 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000183 Hom.: 0

Bravo AF: 0.000170

ExAC AF: 0.000206 AC: 25

EpiCase AF: 0.000436

EpiControl AF: 0.000296

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.046
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	0.20
DANN	Benign	0.26
DEOGEN2	Benign	0.081	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.19	T
M_CAP	Benign	0.0023	T
MetaRNN	Benign	0.015	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-0.42	N
PhyloP100		0.072
PrimateAI	Benign	0.21	T
PROVEAN	Benign	0.90	N
REVEL	Benign	0.023
Sift	Benign	0.60	T
Sift4G	Benign	0.48	T
Polyphen		0.0	B
Vest4		0.063
MutPred		0.36		Gain of glycosylation at S644 (P = 0.0624)
MVP		0.15
MPC		0.089
ClinPred		0.0087	T
GERP RS		-0.11
Varity_R		0.25
gMVP		0.34
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs200727604; hg19: chr3-46479586;