19-19257920-G-A

Variant names:

• chr19-19257920-G-A
• rs1470707970
• NM_023002.3:c.1106C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_023002.3(HAPLN4):​c.1106C>T​(p.Ala369Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000739 in 1,353,700 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.4e-7 (0 hom.)
• Consequence: HAPLN4 NM_023002.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.51
• Publications: 0 publications found

Genes affected

HAPLN4 (HGNC:31357): (hyaluronan and proteoglycan link protein 4) Predicted to enable hyaluronic acid binding activity. Predicted to be involved in central nervous system development and skeletal system development. Predicted to be located in extracellular region. Predicted to be active in extracellular matrix. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000267629 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.112332314).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_023002.3. 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
	HAPLN4	NM_023002.3	MANE Select	c.1106C>T	p.Ala369Val	missense	Exon 5 of 5	NP_075378.1	Q86UW8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HAPLN4	ENST00000291481.8	TSL:1 MANE Select	c.1106C>T	p.Ala369Val	missense	Exon 5 of 5	ENSP00000291481.5	Q86UW8
	HAPLN4	ENST00000898464.1		c.1178C>T	p.Ala393Val	missense	Exon 5 of 5	ENSP00000568523.1
	HAPLN4	ENST00000898466.1		c.1004C>T	p.Ala335Val	missense	Exon 5 of 5	ENSP00000568525.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000897 AC: 1 AN: 111536 AF XY: 0.0000160

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000499

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 7.39e-7 AC: 1 AN: 1353700 Hom.: 0 Cov.: 31 AF XY: 0.00000150 AC XY: 1 AN XY: 668480

African (AFR) AF: 0.00 AC: 0 AN: 28218

American (AMR) AF: 0.0000317 AC: 1 AN: 31564

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23700

East Asian (EAS) AF: 0.00 AC: 0 AN: 32616

South Asian (SAS) AF: 0.00 AC: 0 AN: 75996

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33664

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5354

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1066298

Other (OTH) AF: 0.00 AC: 0 AN: 56290

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	Benign	0.098
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Benign	0.020	T
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.73
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.058	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.34	N
PhyloP100		1.5
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-0.62	N
REVEL	Benign	0.060
Sift	Benign	0.28	T
Sift4G	Benign	0.15	T
Polyphen		0.028	B
Vest4		0.35
MutPred		0.26		Loss of glycosylation at P367 (P = 0.0618)
MVP		0.44
MPC		0.73
ClinPred		0.24	T
GERP RS		4.3
Varity_R		0.069
gMVP		0.32
Mutation Taster		=92/8	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: rs1470707970; hg19: chr19-19368729;