5-83644586-C-G

Variant names:

• chr5-83644586-C-G
• NM_001884.4:c.552G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001884.4(HAPLN1):​c.552G>C​(p.Gln184His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000701 in 1,426,178 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: HAPLN1 NM_001884.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.40
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001884.4. 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
	HAPLN1	NM_001884.4	MANE Select	c.552G>C	p.Gln184His	missense	Exon 4 of 5	NP_001875.1	P10915

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HAPLN1	ENST00000274341.9	TSL:1 MANE Select	c.552G>C	p.Gln184His	missense	Exon 4 of 5	ENSP00000274341.4	P10915
	HAPLN1	ENST00000875523.1		c.552G>C	p.Gln184His	missense	Exon 5 of 6	ENSP00000545582.1
	HAPLN1	ENST00000936313.1		c.552G>C	p.Gln184His	missense	Exon 4 of 5	ENSP00000606372.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.01e-7 AC: 1 AN: 1426178 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 706740

African (AFR) AF: 0.00 AC: 0 AN: 31906

American (AMR) AF: 0.00 AC: 0 AN: 39104

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24264

East Asian (EAS) AF: 0.00 AC: 0 AN: 38366

South Asian (SAS) AF: 0.00 AC: 0 AN: 81082

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52778

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5622

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1094264

Other (OTH) AF: 0.0000170 AC: 1 AN: 58792

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Uncertain	0.018	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.85	T
M_CAP	Benign	0.034	D
MetaRNN	Uncertain	0.64	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		1.4
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-4.7	D
REVEL	Benign	0.23
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.013	D
Polyphen		1.0	D
Vest4		0.76
MutPred		0.56		Gain of catalytic residue at D185 (P = 0.1333)
MVP		0.70
MPC		0.65
ClinPred		0.99	D
GERP RS		2.1
Varity_R		0.83
gMVP		0.78
Mutation Taster		=47/53	disease causing

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

Other links and lift over

hg19: chr5-82940405;