5-83644413-T-G

Position:

• chr5-83644413-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001884.4(HAPLN1):​c.725A>C​(p.Asp242Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: HAPLN1 NM_001884.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.67

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 Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HAPLN1	NM_001884.4	c.725A>C	p.Asp242Ala	missense_variant	4/5	ENST00000274341.9	NP_001875.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HAPLN1	ENST00000274341.9	c.725A>C	p.Asp242Ala	missense_variant	4/5	1	NM_001884.4	ENSP00000274341.4
HAPLN1	ENST00000510978.5	c.725A>C	p.Asp242Ala	missense_variant	3/3	2		ENSP00000422592.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 25, 2024

The c.725A>C (p.D242A) alteration is located in exon 4 (coding exon 3) of the HAPLN1 gene. This alteration results from a A to C substitution at nucleotide position 725, causing the aspartic acid (D) at amino acid position 242 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	0.29
BayesDel_addAF	Benign	-0.070	T
BayesDel_noAF	Benign	-0.34
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.26	T;T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D;T
M_CAP	Benign	0.024	T
MetaRNN	Uncertain	0.63	D;D
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.1	M;.
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-3.9	D;D
REVEL	Benign	0.24
Sift	Benign	0.055	T;D
Sift4G	Benign	0.081	T;.
Polyphen		0.62	P;.
Vest4		0.67
MutPred		0.54		Gain of methylation at K243 (P = 0.0474);Gain of methylation at K243 (P = 0.0474);
MVP		0.62
MPC		0.39
ClinPred		0.98	D
GERP RS		5.5
Varity_R		0.47
gMVP		0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-82940232;