Genetic Variant HAPLN4:p.Gly326Ser (chr19-19258050-C-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_023002.3(HAPLN4):c.976G>A(p.Gly326Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. G326C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

HAPLN4
NM_023002.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.45

Publications

0 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:

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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, 0.929

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.976G>A	p.Gly326Ser	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.976G>A	p.Gly326Ser	missense	Exon 5 of 5	ENSP00000291481.5	Q86UW8
HAPLN4	ENST00000898464.1		c.1048G>A	p.Gly350Ser	missense	Exon 5 of 5	ENSP00000568523.1
HAPLN4	ENST00000898466.1		c.874G>A	p.Gly292Ser	missense	Exon 5 of 5	ENSP00000568525.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1397702

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

690726

African (AFR)

AF:

0.00

AC:

AN:

31996

American (AMR)

AF:

0.00

AC:

AN:

38848

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25194

East Asian (EAS)

AF:

0.00

AC:

AN:

36840

South Asian (SAS)

AF:

0.00

AC:

AN:

80740

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34366

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5588

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1085998

Other (OTH)

AF:

0.00

AC:

AN:

58132

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.33

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

-0.060

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.28

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

M_CAP

Uncertain

0.13

MetaRNN

Pathogenic

0.93

MetaSVM

Uncertain

-0.071

MutationAssessor

Pathogenic

3.6

PhyloP100

7.4

PrimateAI

Pathogenic

0.82

PROVEAN

Pathogenic

-4.8

REVEL

Uncertain

0.49

Sift

Uncertain

0.0080

Sift4G

Uncertain

0.035

Polyphen

1.0

Vest4

0.68

MutPred

0.80

Loss of sheet (P = 0.0817)

MVP

0.84

MPC

1.6

ClinPred

1.0

GERP RS

4.0

Varity_R

0.70

gMVP

0.73

Mutation Taster

=53/47

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