Genetic Variant HTN3:p.Arg41Gln (chr4-70033186-G-A) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 2P and 12B. PM1BP4_StrongBA1

The NM_000200.3(HTN3):c.122G>A(p.Arg41Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00808 in 1,605,536 control chromosomes in the GnomAD database, including 931 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as no classification for the single variant (no stars).

Frequency

Genomes: 𝑓 0.044 ( 506 hom., cov: 32)

Exomes 𝑓: 0.0043 ( 425 hom. )

Consequence

HTN3
NM_000200.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.61

Publications

2 publications found

Variant links:

Genes affected

HTN3 (HGNC:5284): (histatin 3) This gene encodes a member of the histatin family of small, histidine-rich, cationic proteins. They function as antimicrobial peptides and are important components of the innate immune system. Histatins are found in saliva and exhibit antibacterial, antifungal activities and function in wound healing. [provided by RefSeq, Sep 2014]

HTN3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

PM1

In a mutagenesis_site 10-fold reduction in candidacidal activity of His3-(20-43)-peptide; when associated with E-32. (size 0) in uniprot entity HIS3_HUMAN

BP4

Computational evidence support a benign effect (MetaRNN=0.0015038848).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.151 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HTN3	NM_000200.3 link	c.122G>A	p.Arg41Gln	missense_variant	Exon 5 of 6	ENST00000673563.1	NP_000191.1	P15516

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HTN3	ENST00000673563.1 link	c.122G>A	p.Arg41Gln	missense_variant	Exon 5 of 6		NM_000200.3	ENSP00000500623.1		P15516

Frequencies

GnomAD3 genomes

AF:

0.0444

AC:

6745

AN:

151908

Hom.:

503

Cov.:

show subpopulations

Gnomad AFR

AF:

0.154

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0162

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00664

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00637

Gnomad NFE

AF:

0.000235

Gnomad OTH

AF:

0.0321

GnomAD2 exomes

AF:

0.0111

AC:

2760

AN:

248408

AF XY:

0.00806

show subpopulations

Gnomad AFR exome

AF:

0.152

Gnomad AMR exome

AF:

0.00575

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000221

Gnomad OTH exome

AF:

0.00315

GnomAD4 exome

AF:

0.00428

AC:

6220

AN:

1453510

Hom.:

425

Cov.:

AF XY:

0.00373

AC XY:

2699

AN XY:

723328

show subpopulations

African (AFR)

AF:

0.149

AC:

4870

AN:

32578

American (AMR)

AF:

0.00712

AC:

315

AN:

44244

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26054

East Asian (EAS)

AF:

0.000101

AC:

AN:

39486

South Asian (SAS)

AF:

0.00373

AC:

318

AN:

85258

European-Finnish (FIN)

AF:

0.0000188

AC:

AN:

53292

Middle Eastern (MID)

AF:

0.00487

AC:

AN:

5746

European-Non Finnish (NFE)

AF:

0.0000822

AC:

AN:

1106752

Other (OTH)

AF:

0.00987

AC:

593

AN:

60100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.426

Heterozygous variant carriers

218

435

653

870

1088

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

144

288

432

576

720

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0445

AC:

6759

AN:

152026

Hom.:

506

Cov.:

AF XY:

0.0430

AC XY:

3194

AN XY:

74310

show subpopulations

African (AFR)

AF:

0.154

AC:

6399

AN:

41462

American (AMR)

AF:

0.0161

AC:

246

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3460

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.00623

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10574

Middle Eastern (MID)

AF:

0.00342

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000235

AC:

AN:

67956

Other (OTH)

AF:

0.0318

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

294

589

883

1178

1472

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

192

256

320

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0344

Hom.:

414

Bravo

AF:

0.0501

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.146

AC:

642

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.0143

AC:

1732

Asia WGS

AF:

0.0110

AC:

AN:

3476

EpiCase

AF:

0.000219

EpiControl

AF:

0.000179

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.72

BayesDel_noAF

Benign

-0.67

CADD

Benign

0.69

(source)

DANN

Benign

0.37

DEOGEN2

Benign

0.0057

T;T;T

Eigen

Benign

-0.84

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.0032

MetaRNN

Benign

0.0015

T;T;T

MetaSVM

Benign

-1.1

PhyloP100

-1.6

PrimateAI

Benign

0.24

PROVEAN

Uncertain

-2.7

D;D;D

REVEL

Benign

0.073

Sift

Benign

0.079

T;T;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

0.54

P;P;.

Vest4

0.16

MPC

0.024

ClinPred

0.019

GERP RS

0.31

Varity_R

0.053

gMVP

0.022

Mutation Taster

=96/4

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over