Genetic Variant HAPLN4:p.Gly386Ser (chr19-19257870-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_023002.3(HAPLN4):c.1156G>A(p.Gly386Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 151,966 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 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

HAPLN4
NM_023002.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.520

Publications

1 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.09356108).

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.1156G>A	p.Gly386Ser	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.1156G>A	p.Gly386Ser	missense	Exon 5 of 5	ENSP00000291481.5	Q86UW8
HAPLN4	ENST00000898464.1		c.1228G>A	p.Gly410Ser	missense	Exon 5 of 5	ENSP00000568523.1
HAPLN4	ENST00000898466.1		c.1054G>A	p.Gly352Ser	missense	Exon 5 of 5	ENSP00000568525.1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

151966

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1279160

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

628124

African (AFR)

AF:

0.00

AC:

AN:

25542

American (AMR)

AF:

0.00

AC:

AN:

17302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19236

East Asian (EAS)

AF:

0.00

AC:

AN:

30706

South Asian (SAS)

AF:

0.00

AC:

AN:

63144

European-Finnish (FIN)

AF:

0.00

AC:

AN:

31702

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4142

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1034552

Other (OTH)

AF:

0.00

AC:

AN:

52834

GnomAD4 genome

AF:

0.00000658

AC:

AN:

151966

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74246

show subpopulations

African (AFR)

AF:

0.0000242

AC:

AN:

41394

American (AMR)

AF:

0.00

AC:

AN:

15260

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:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10592

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67938

Other (OTH)

AF:

0.00

AC:

AN:

2086

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

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

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

0.13

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.60

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.015

Eigen

Benign

-0.47

Eigen_PC

Benign

-0.36

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.66

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.094

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.55

PhyloP100

0.52

PrimateAI

Pathogenic

0.89

PROVEAN

Benign

-0.51

REVEL

Benign

0.098

Sift

Pathogenic

0.0

Sift4G

Benign

0.14

Polyphen

0.046

Vest4

0.27

MutPred

0.33

Gain of glycosylation at G386 (P = 0.0092)

MVP

0.43

MPC

0.69

ClinPred

0.56

GERP RS

3.5

Varity_R

0.21

gMVP

0.65

Mutation Taster

=96/4

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over