Genetic Variant NM_001884.4:c.485C>T (chr5-83644653-G-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PP3_ModerateBS2

The NM_001884.4(HAPLN1):c.485C>T(p.Pro162Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000759 in 1,317,724 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000076 ( 0 hom. )

Consequence

HAPLN1
NM_001884.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

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: Likely_benign. The variant received -2 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.92

BS2

High AC in GnomAdExome4 at 10 AD gene.

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>T	p.Pro162Leu	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>T	p.Pro162Leu	missense	Exon 4 of 5	ENSP00000274341.4	P10915
HAPLN1	ENST00000875523.1		c.485C>T	p.Pro162Leu	missense	Exon 5 of 6	ENSP00000545582.1
HAPLN1	ENST00000936313.1		c.485C>T	p.Pro162Leu	missense	Exon 4 of 5	ENSP00000606372.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000660

AC:

AN:

151580

AF XY:

0.0000124

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.0000133

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000759

AC:

AN:

1317724

Hom.:

Cov.:

AF XY:

0.00000932

AC XY:

AN XY:

643640

show subpopulations

African (AFR)

AF:

0.0000357

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:

0.00000770

AC:

AN:

1038626

Other (OTH)

AF:

0.00

AC:

AN:

53908

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

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.:

ExAC

AF:

0.00000838

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

Pathogenic

0.76

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Uncertain

0.070

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.37

Eigen

Pathogenic

0.75

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.86

M_CAP

Benign

0.060

MetaRNN

Pathogenic

0.92

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.4

PhyloP100

9.6

PrimateAI

Pathogenic

0.81

PROVEAN

Pathogenic

-9.5

REVEL

Uncertain

0.55

Sift

Pathogenic

0.0

Sift4G

Benign

0.078

Polyphen

1.0

Vest4

0.94

MutPred

0.80

Loss of catalytic residue at P162 (P = 0.2718)

MVP

0.71

MPC

0.48

ClinPred

1.0

GERP RS

5.8

Varity_R

0.91

gMVP

0.76

Mutation Taster

=16/84

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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