5-83644633-G-A

Variant names:

• chr5-83644633-G-A
• rs773994130
• NM_001884.4:c.505C>T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP3_Moderate BS2

The NM_001884.4(HAPLN1):​c.505C>T​(p.Arg169Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000898 in 1,336,786 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: 0.0000090 (0 hom.)
• Consequence: HAPLN1 NM_001884.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.71

Genes affected

HAPLN1 (HGNC:2380): (hyaluronan and proteoglycan link protein 1) Predicted to enable hyaluronic acid binding activity. Predicted to be an extracellular matrix structural constituent conferring compression resistance. Predicted to be involved in central nervous system development and skeletal system development. Colocalizes with collagen-containing extracellular matrix. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.921
• BS2: High AC in GnomAdExome4 at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HAPLN1	NM_001884.4	c.505C>T	p.Arg169Cys	missense_variant	Exon 4 of 5	ENST00000274341.9	NP_001875.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HAPLN1	ENST00000274341.9	c.505C>T	p.Arg169Cys	missense_variant	Exon 4 of 5	1	NM_001884.4	ENSP00000274341.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000123 AC: 2 AN: 162216 Hom.: 0 AF XY: 0.0000232 AC XY: 2 AN XY: 86378

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: 0.0000251

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000898 AC: 12 AN: 1336786 Hom.: 0 Cov.: 36 AF XY: 0.0000107 AC XY: 7 AN XY: 654642

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: 0.0000600

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000668

Gnomad4 OTH exome AF: 0.0000183

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000151

ExAC AF: 0.00000829 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 15, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.505C>T (p.R169C) alteration is located in exon 4 (coding exon 3) of the HAPLN1 gene. This alteration results from a C to T substitution at nucleotide position 505, causing the arginine (R) at amino acid position 169 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	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.47	T;T;T;T;T
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D
MetaSVM	Benign	-0.44	T
MutationAssessor	Pathogenic	3.8	H;.;.;.;.
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-7.7	D;D;D;D;.
REVEL	Uncertain	0.64
Sift	Pathogenic	0.0	D;D;D;D;.
Sift4G	Pathogenic	0.0	D;.;D;.;.
Polyphen		1.0	D;.;.;.;.
Vest4		0.83
MutPred		0.79		Loss of methylation at R169 (P = 0.0638);Loss of methylation at R169 (P = 0.0638);Loss of methylation at R169 (P = 0.0638);.;Loss of methylation at R169 (P = 0.0638);
MVP		0.67
MPC		0.79
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.82
gMVP		0.85

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

Other links and lift over

dbSNP: rs773994130; hg19: chr5-82940452; COSMIC: COSV99164506;