19-19257860-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_023002.3(HAPLN4):​c.1166G>C​(p.Gly389Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000367 in 1,281,242 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.000037 ( 0 hom. )

Consequence

HAPLN4
NM_023002.3 missense

Scores

3
1
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.64
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.07427806).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
HAPLN4NM_023002.3 linkc.1166G>C p.Gly389Ala missense_variant Exon 5 of 5 ENST00000291481.8 NP_075378.1 Q86UW8

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
HAPLN4ENST00000291481.8 linkc.1166G>C p.Gly389Ala missense_variant Exon 5 of 5 1 NM_023002.3 ENSP00000291481.5 Q86UW8
ENSG00000267629ENST00000586064.3 linkn.2297G>C non_coding_transcript_exon_variant Exon 12 of 12 2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.0000365
AC:
2
AN:
54720
Hom.:
0
AF XY:
0.0000319
AC XY:
1
AN XY:
31330
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:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000725
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000367
AC:
47
AN:
1281242
Hom.:
0
Cov.:
31
AF XY:
0.0000413
AC XY:
26
AN XY:
629298
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000577
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000415
Gnomad4 OTH exome
AF:
0.0000567
GnomAD4 genome
Cov.:
32
ExAC
AF:
0.0000205
AC:
2

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Jan 23, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1166G>C (p.G389A) alteration is located in exon 5 (coding exon 5) of the HAPLN4 gene. This alteration results from a G to C substitution at nucleotide position 1166, causing the glycine (G) at amino acid position 389 to be replaced by an alanine (A). 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
0.092
BayesDel_addAF
Benign
-0.31
T
BayesDel_noAF
Benign
-0.50
CADD
Benign
21
DANN
Uncertain
0.98
DEOGEN2
Benign
0.018
T
Eigen
Benign
-0.69
Eigen_PC
Benign
-0.65
FATHMM_MKL
Benign
0.25
N
LIST_S2
Benign
0.64
T
M_CAP
Benign
0.067
D
MetaRNN
Benign
0.074
T
MetaSVM
Benign
-0.96
T
MutationAssessor
Benign
0.0
N
PrimateAI
Pathogenic
0.87
D
PROVEAN
Benign
-0.54
N
REVEL
Benign
0.059
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0
D
Polyphen
0.043
B
Vest4
0.33
MutPred
0.24
Loss of loop (P = 0.0374);
MVP
0.35
MPC
0.75
ClinPred
0.27
T
GERP RS
2.5
Varity_R
0.18
gMVP
0.70

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.

Other links and lift over

dbSNP: rs767317493; hg19: chr19-19368669; API