5-83644444-C-T

Position:

• chr5-83644444-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001884.4(HAPLN1):​c.694G>A​(p.Val232Met) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HAPLN1 NM_001884.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.74

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30074942).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HAPLN1	NM_001884.4	c.694G>A	p.Val232Met	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.694G>A	p.Val232Met	missense_variant	4/5	1	NM_001884.4	ENSP00000274341.4
HAPLN1	ENST00000510978.5	c.694G>A	p.Val232Met	missense_variant	3/3	2		ENSP00000422592.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000806 AC: 2 AN: 248024 Hom.: 1 AF XY: 0.00 AC XY: 0 AN XY: 134248

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000110

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000165 AC: 2

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

Oct 20, 2024

The c.694G>A (p.V232M) alteration is located in exon 4 (coding exon 3) of the HAPLN1 gene. This alteration results from a G to A substitution at nucleotide position 694, causing the valine (V) at amino acid position 232 to be replaced by a methionine (M). 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	0.14
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T;T
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.81	T;T
M_CAP	Benign	0.0058	T
MetaRNN	Benign	0.30	T;T
MetaSVM	Benign	-1.2	T
MutationAssessor	Benign	0.55	N;.
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-0.36	N;N
REVEL	Benign	0.11
Sift	Benign	0.051	T;T
Sift4G	Benign	0.23	T;.
Polyphen		0.74	P;.
Vest4		0.56
MutPred		0.47		Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);
MVP		0.53
MPC		0.30
ClinPred		0.51	D
GERP RS		5.5
Varity_R		0.074
gMVP		0.49

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: rs771312352; hg19: chr5-82940263;