NM_178232.4:c.1057G>C

Variant names:

• chr15-88877996-C-G
• rs769012368
• NM_178232.4:c.1057G>C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_178232.4(HAPLN3):​c.1057G>C​(p.Gly353Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000754 in 1,459,842 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: HAPLN3 NM_178232.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.45

Genes affected

HAPLN3 (HGNC:21446): (hyaluronan and proteoglycan link protein 3) This gene belongs to the hyaluronan and proteoglycan binding link protein gene family. The protein encoded by this gene may function in hyaluronic acid binding and cell adhesion. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.933

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HAPLN3	NM_178232.4	c.1057G>C	p.Gly353Arg	missense_variant	Exon 5 of 5	ENST00000359595.8	NP_839946.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HAPLN3	ENST00000359595.8	c.1057G>C	p.Gly353Arg	missense_variant	Exon 5 of 5	1	NM_178232.4	ENSP00000352606.4
HAPLN3	ENST00000562889.5	c.1243G>C	p.Gly415Arg	missense_variant	Exon 6 of 6	5		ENSP00000457180.1
HAPLN3	ENST00000558770.5	n.*1689G>C		non_coding_transcript_exon_variant	Exon 6 of 6	2		ENSP00000456458.1
HAPLN3	ENST00000558770.5	n.*1689G>C		3_prime_UTR_variant	Exon 6 of 6	2		ENSP00000456458.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000442 AC: 11 AN: 248730 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 134738

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000320

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000754 AC: 11 AN: 1459842 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 726192

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000247

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000151

ExAC AF: 0.0000330 AC: 4

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Benign	-0.037	T
BayesDel_noAF	Uncertain	0.010
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T;.
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Benign	0.063	D
MetaRNN	Pathogenic	0.93	D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.7	M;.
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-6.8	D;D
REVEL	Uncertain	0.43
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0030	D;D
Polyphen		1.0	D;.
Vest4		0.81
MutPred		0.82		Gain of MoRF binding (P = 0.0021);.;
MVP		0.33
MPC		0.88
ClinPred		0.96	D
GERP RS		3.6
Varity_R		0.72
gMVP		0.89

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: rs769012368; hg19: chr15-89421227;