Genetic Variant HAPLN3:p.Tyr352Cys (chr15-88877998-T-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_178232.4(HAPLN3):c.1055A>G(p.Tyr352Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,630 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

HAPLN3
NM_178232.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.74

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 made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HAPLN3	NM_178232.4 link	c.1055A>G	p.Tyr352Cys	missense_variant	Exon 5 of 5	ENST00000359595.8	NP_839946.1	Q96S86A0A024RC58A8K7T8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
HAPLN3	ENST00000359595.8 link	c.1055A>G	p.Tyr352Cys	missense_variant	Exon 5 of 5	1	NM_178232.4	ENSP00000352606.4	Q96S86
HAPLN3	ENST00000562889.5 link	c.1241A>G	p.Tyr414Cys	missense_variant	Exon 6 of 6	5		ENSP00000457180.1	H3BTH8
HAPLN3	ENST00000558770.5 link	n.*1687A>G		non_coding_transcript_exon_variant	Exon 6 of 6	2		ENSP00000456458.1	H3BRY4
HAPLN3	ENST00000558770.5 link	n.*1687A>G		3_prime_UTR_variant	Exon 6 of 6	2		ENSP00000456458.1	H3BRY4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000401

AC:

AN:

249406

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135066

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 SAS exome

AF:

0.0000328

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460630

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726598

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 08, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1055A>G (p.Y352C) alteration is located in exon 5 (coding exon 4) of the HAPLN3 gene. This alteration results from a A to G substitution at nucleotide position 1055, causing the tyrosine (Y) at amino acid position 352 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.54

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.30

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.25

T;.

Eigen

Uncertain

0.24

Eigen_PC

Benign

-0.014

FATHMM_MKL

Benign

0.68

LIST_S2

Uncertain

0.97

D;D

M_CAP

Benign

0.026

MetaRNN

Uncertain

0.66

D;D

MetaSVM

Benign

-0.79

MutationAssessor

Pathogenic

3.5

M;.

PrimateAI

Uncertain

0.52

PROVEAN

Pathogenic

-6.5

D;D

REVEL

Benign

0.12

Sift

Uncertain

0.0010

D;D

Sift4G

Uncertain

0.0040

D;D

Polyphen

1.0

D;.

Vest4

0.24

MutPred

0.85

Gain of disorder (P = 0.0473);.;

MVP

0.63

MPC

0.86

ClinPred

0.91

GERP RS

2.0

Varity_R

0.36

gMVP

0.89

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over