15-88879056-G-A

Variant names:

• chr15-88879056-G-A
• rs935884458
• NM_178232.4:c.707C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_178232.4(HAPLN3):​c.707C>T​(p.Pro236Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000623 in 1,606,066 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P236S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: HAPLN3 NM_178232.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.104
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05084625).
• BP6: Variant 15-88879056-G-A is Benign according to our data. Variant chr15-88879056-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 2604666.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_178232.4. 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
	HAPLN3	NM_178232.4	MANE Select	c.707C>T	p.Pro236Leu	missense	Exon 4 of 5	NP_839946.1	Q96S86
	HAPLN3	NM_001307952.2		c.893C>T	p.Pro298Leu	missense	Exon 5 of 6	NP_001294881.1	H3BTH8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HAPLN3	ENST00000359595.8	TSL:1 MANE Select	c.707C>T	p.Pro236Leu	missense	Exon 4 of 5	ENSP00000352606.4	Q96S86
	HAPLN3	ENST00000562889.5	TSL:5	c.893C>T	p.Pro298Leu	missense	Exon 5 of 6	ENSP00000457180.1	H3BTH8
	HAPLN3	ENST00000969266.1		c.749C>T	p.Pro250Leu	missense	Exon 5 of 6	ENSP00000639325.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152242 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000219 AC: 5 AN: 228818 AF XY: 0.0000159

Gnomad AFR exome AF: 0.0000716

Gnomad AMR exome AF: 0.0000304

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000299

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000482 AC: 7 AN: 1453708 Hom.: 0 Cov.: 33 AF XY: 0.00000415 AC XY: 3 AN XY: 722632

African (AFR) AF: 0.00 AC: 0 AN: 33332

American (AMR) AF: 0.0000229 AC: 1 AN: 43612

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25852

East Asian (EAS) AF: 0.00 AC: 0 AN: 39414

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85342

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51772

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 0.00000451 AC: 5 AN: 1108634

Other (OTH) AF: 0.00 AC: 0 AN: 60000

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152358 Hom.: 0 Cov.: 33 AF XY: 0.0000268 AC XY: 2 AN XY: 74510

African (AFR) AF: 0.0000240 AC: 1 AN: 41584

American (AMR) AF: 0.00 AC: 0 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000227

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

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	Benign	0.056
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	11
DANN	Benign	0.89
DEOGEN2	Benign	0.0082	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.0038	N
LIST_S2	Benign	0.43	T
M_CAP	Benign	0.0062	T
MetaRNN	Benign	0.051	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-2.1	N
PhyloP100		0.10
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.051
Sift	Benign	0.36	T
Sift4G	Benign	0.33	T
Polyphen		0.0	B
Vest4		0.15
MutPred		0.51		Loss of disorder (P = 0.0204)
MVP		0.17
MPC		0.21
ClinPred		0.020	T
GERP RS		-0.12
Varity_R		0.020
gMVP		0.13
Mutation Taster		=94/6	polymorphism

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

dbSNP: rs935884458; hg19: chr15-89422287;