Genetic Variant HAPLN4:p.Arg282Gln (chr19-19258181-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_023002.3(HAPLN4):c.845G>A(p.Arg282Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000186 in 1,514,958 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00019 ( 0 hom. )

Consequence

HAPLN4
NM_023002.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.524

Publications

0 publications found

Variant links:

Genes affected

HAPLN4 (HGNC:31357): (hyaluronan and proteoglycan link protein 4) Predicted to enable hyaluronic acid binding activity. Predicted to be involved in central nervous system development and skeletal system development. Predicted to be located in extracellular region. Predicted to be active in extracellular matrix. [provided by Alliance of Genome Resources, Apr 2022]

HAPLN4 links:

ENSG00000267629 (HGNC:):

ENSG00000267629 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.08043036).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_023002.3. 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
	HAPLN4	NM_023002.3	MANE Select	c.845G>A	p.Arg282Gln	missense	Exon 5 of 5	NP_075378.1	Q86UW8

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HAPLN4	ENST00000291481.8	TSL:1 MANE Select	c.845G>A	p.Arg282Gln	missense	Exon 5 of 5	ENSP00000291481.5	Q86UW8
HAPLN4	ENST00000898464.1		c.917G>A	p.Arg306Gln	missense	Exon 5 of 5	ENSP00000568523.1
HAPLN4	ENST00000898466.1		c.743G>A	p.Arg248Gln	missense	Exon 5 of 5	ENSP00000568525.1

Frequencies

GnomAD3 genomes

AF:

0.000125

AC:

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000279

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000112

AC:

AN:

133624

AF XY:

0.0000941

show subpopulations

Gnomad AFR exome

AF:

0.000124

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000245

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000193

AC:

263

AN:

1362682

Hom.:

Cov.:

AF XY:

0.000199

AC XY:

133

AN XY:

668402

show subpopulations

African (AFR)

AF:

0.000128

AC:

AN:

31328

American (AMR)

AF:

0.0000629

AC:

AN:

31798

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23574

East Asian (EAS)

AF:

0.00

AC:

AN:

36774

South Asian (SAS)

AF:

0.00

AC:

AN:

76726

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33954

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5496

European-Non Finnish (NFE)

AF:

0.000234

AC:

249

AN:

1066254

Other (OTH)

AF:

0.000141

AC:

AN:

56778

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.000125

AC:

AN:

152276

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74448

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41560

American (AMR)

AF:

0.00

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000279

AC:

AN:

68012

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000239

Hom.:

Bravo

AF:

0.000166

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000408

AC:

ExAC

AF:

0.000116

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.61

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0083

Eigen

Benign

-0.12

Eigen_PC

Benign

-0.13

FATHMM_MKL

Benign

0.027

LIST_S2

Benign

0.72

M_CAP

Benign

0.031

MetaRNN

Benign

0.080

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.2

PhyloP100

0.52

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

-0.41

REVEL

Benign

0.048

Sift

Benign

0.27

Sift4G

Benign

0.43

Polyphen

0.84

Vest4

0.14

MVP

0.50

MPC

1.3

ClinPred

0.090

GERP RS

4.0

Varity_R

0.10

gMVP

0.45

Mutation Taster

=95/5

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over