19-19258660-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_023002.3(HAPLN4):​c.680G>A​(p.Arg227Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000048 in 1,458,194 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: 32)
Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

HAPLN4
NM_023002.3 missense

Scores

6
7
6

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.42
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.882

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
HAPLN4NM_023002.3 linkc.680G>A p.Arg227Gln missense_variant Exon 4 of 5 ENST00000291481.8 NP_075378.1 Q86UW8

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
HAPLN4ENST00000291481.8 linkc.680G>A p.Arg227Gln missense_variant Exon 4 of 5 1 NM_023002.3 ENSP00000291481.5 Q86UW8
ENSG00000267629ENST00000586064.3 linkn.1811G>A non_coding_transcript_exon_variant Exon 11 of 12 2
HAPLN4ENST00000592862.2 linkn.*186G>A downstream_gene_variant 5

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000838
AC:
2
AN:
238548
Hom.:
0
AF XY:
0.0000153
AC XY:
2
AN XY:
130406
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:
0.0000330
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000944
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000480
AC:
7
AN:
1458194
Hom.:
0
Cov.:
33
AF XY:
0.00000552
AC XY:
4
AN XY:
725290
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:
0.0000581
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000180
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000378

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Dec 11, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.680G>A (p.R227Q) alteration is located in exon 4 (coding exon 4) of the HAPLN4 gene. This alteration results from a G to A substitution at nucleotide position 680, causing the arginine (R) at amino acid position 227 to be replaced by a glutamine (Q). 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
Benign
0.28
BayesDel_addAF
Benign
-0.017
T
BayesDel_noAF
Benign
-0.16
CADD
Pathogenic
32
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.30
T
Eigen
Pathogenic
0.74
Eigen_PC
Uncertain
0.56
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.97
D
M_CAP
Uncertain
0.13
D
MetaRNN
Pathogenic
0.88
D
MetaSVM
Benign
-0.45
T
MutationAssessor
Pathogenic
4.2
H
PrimateAI
Uncertain
0.69
T
PROVEAN
Uncertain
-3.7
D
REVEL
Uncertain
0.43
Sift
Pathogenic
0.0
D
Sift4G
Uncertain
0.0030
D
Polyphen
1.0
D
Vest4
0.71
MutPred
0.72
Loss of glycosylation at P226 (P = 0.0769);
MVP
0.68
MPC
1.9
ClinPred
1.0
D
GERP RS
4.0
Varity_R
0.81
gMVP
0.86

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
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.

Other links and lift over

dbSNP: rs891875500; hg19: chr19-19369469; COSMIC: COSV52268956; COSMIC: COSV52268956; API