Genetic Variant HAPLN1:p.Pro162His (chr5-83644653-G-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001884.4(HAPLN1):c.485C>A(p.Pro162His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000759 in 1,317,724 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P162L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.6e-7 ( 0 hom. )

Consequence

HAPLN1
NM_001884.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.57

Publications

0 publications found

Variant links:

Genes affected

HAPLN1 (HGNC:2380): (hyaluronan and proteoglycan link protein 1) Predicted to enable hyaluronic acid binding activity. Predicted to be an extracellular matrix structural constituent conferring compression resistance. Predicted to be involved in central nervous system development and skeletal system development. Colocalizes with collagen-containing extracellular matrix. [provided by Alliance of Genome Resources, Apr 2022]

HAPLN1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.874

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001884.4. 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
	HAPLN1	NM_001884.4	MANE Select	c.485C>A	p.Pro162His	missense	Exon 4 of 5	NP_001875.1	P10915

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HAPLN1	ENST00000274341.9	TSL:1 MANE Select	c.485C>A	p.Pro162His	missense	Exon 4 of 5	ENSP00000274341.4	P10915
HAPLN1	ENST00000875523.1		c.485C>A	p.Pro162His	missense	Exon 5 of 6	ENSP00000545582.1
HAPLN1	ENST00000936313.1		c.485C>A	p.Pro162His	missense	Exon 4 of 5	ENSP00000606372.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.59e-7

AC:

AN:

1317724

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

643640

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

27978

American (AMR)

AF:

0.00

AC:

AN:

26140

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19098

East Asian (EAS)

AF:

0.00

AC:

AN:

34822

South Asian (SAS)

AF:

0.0000158

AC:

AN:

63350

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48796

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5006

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1038626

Other (OTH)

AF:

0.00

AC:

AN:

53908

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.75

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Uncertain

0.040

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.35

Eigen

Pathogenic

0.76

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.86

M_CAP

Benign

0.036

MetaRNN

Pathogenic

0.87

MetaSVM

Benign

-1.2

MutationAssessor

Benign

0.93

PhyloP100

9.6

PrimateAI

Pathogenic

0.79

PROVEAN

Pathogenic

-8.2

REVEL

Uncertain

0.50

Sift

Pathogenic

0.0

Sift4G

Benign

0.19

Polyphen

1.0

Vest4

0.86

MutPred

0.71

Loss of catalytic residue at P162 (P = 0.1318)

MVP

0.74

MPC

0.34

ClinPred

1.0

GERP RS

5.8

Varity_R

0.91

gMVP

0.72

Mutation Taster

=21/79

disease causing

(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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over