Genetic Variant NM_178232.4:c.707C>A (chr15-88879056-G-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_178232.4(HAPLN3):c.707C>A(p.Pro236Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,453,708 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign 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. P236S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

HAPLN3
NM_178232.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.104

Publications

0 publications found

Variant links:

Genes affected

HAPLN3 (HGNC:21446): (hyaluronan and proteoglycan link protein 3) This gene belongs to the hyaluronan and proteoglycan binding link protein gene family. The protein encoded by this gene may function in hyaluronic acid binding and cell adhesion. [provided by RefSeq, Jul 2008]

HAPLN3 links:

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ACMG classification

Classification was made for transcript

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

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06642482).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_178232.4. 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
	HAPLN3	NM_178232.4	MANE Select	c.707C>A	p.Pro236Gln	missense	Exon 4 of 5	NP_839946.1	Q96S86
	HAPLN3	NM_001307952.2		c.893C>A	p.Pro298Gln	missense	Exon 5 of 6	NP_001294881.1	H3BTH8

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HAPLN3	ENST00000359595.8	TSL:1 MANE Select	c.707C>A	p.Pro236Gln	missense	Exon 4 of 5	ENSP00000352606.4	Q96S86
HAPLN3	ENST00000562889.5	TSL:5	c.893C>A	p.Pro298Gln	missense	Exon 5 of 6	ENSP00000457180.1	H3BTH8
HAPLN3	ENST00000969266.1		c.749C>A	p.Pro250Gln	missense	Exon 5 of 6	ENSP00000639325.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.88e-7

AC:

AN:

1453708

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

722632

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33332

American (AMR)

AF:

0.00

AC:

AN:

43612

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25852

East Asian (EAS)

AF:

0.00

AC:

AN:

39414

South Asian (SAS)

AF:

0.00

AC:

AN:

85342

European-Finnish (FIN)

AF:

0.0000193

AC:

AN:

51772

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5750

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1108634

Other (OTH)

AF:

0.00

AC:

AN:

60000

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.66

CADD

Benign

5.4

(source)

DANN

Benign

0.83

DEOGEN2

Benign

0.0068

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.97

FATHMM_MKL

Benign

0.0055

LIST_S2

Benign

0.56

M_CAP

Benign

0.0081

MetaRNN

Benign

0.066

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.20

PhyloP100

0.10

PrimateAI

Benign

0.44

PROVEAN

Benign

0.71

REVEL

Benign

0.044

Sift

Benign

0.63

Sift4G

Benign

0.58

Polyphen

0.0080

Vest4

0.27

MutPred

0.40

Gain of catalytic residue at P236 (P = 0.0172)

MVP

0.18

MPC

0.34

ClinPred

0.039

GERP RS

-0.12

Varity_R

0.023

gMVP

0.16

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over