chr19-19257998-C-T

Variant names:

• chr19-19257998-C-T
• rs771786704
• NM_023002.3:c.1028G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_023002.3(HAPLN4):​c.1028G>A​(p.Arg343Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000231 in 1,516,488 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00037 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00021 (0 hom.)
• Consequence: HAPLN4 NM_023002.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.86
• 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.025091082).

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.1028G>A	p.Arg343Lys	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.1028G>A	p.Arg343Lys	missense	Exon 5 of 5	ENSP00000291481.5	Q86UW8
	HAPLN4	ENST00000898464.1		c.1100G>A	p.Arg367Lys	missense	Exon 5 of 5	ENSP00000568523.1
	HAPLN4	ENST00000898466.1		c.926G>A	p.Arg309Lys	missense	Exon 5 of 5	ENSP00000568525.1

Frequencies

GnomAD3 genomes AF: 0.000375 AC: 57 AN: 152156 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000982

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000529

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.000313 AC: 38 AN: 121394 AF XY: 0.000293

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000601

Gnomad ASJ exome AF: 0.000289

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000393

Gnomad OTH exome AF: 0.000855

GnomAD4 exome AF: 0.000215 AC: 293 AN: 1364222 Hom.: 0 Cov.: 31 AF XY: 0.000202 AC XY: 136 AN XY: 672722

African (AFR) AF: 0.0000349 AC: 1 AN: 28656

American (AMR) AF: 0.000747 AC: 25 AN: 33478

Ashkenazi Jewish (ASJ) AF: 0.000377 AC: 9 AN: 23890

East Asian (EAS) AF: 0.00 AC: 0 AN: 33962

South Asian (SAS) AF: 0.0000130 AC: 1 AN: 77142

European-Finnish (FIN) AF: 0.0000592 AC: 2 AN: 33760

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5540

European-Non Finnish (NFE) AF: 0.000220 AC: 236 AN: 1071052

Other (OTH) AF: 0.000335 AC: 19 AN: 56742

GnomAD4 genome AF: 0.000374 AC: 57 AN: 152266 Hom.: 0 Cov.: 32 AF XY: 0.000363 AC XY: 27 AN XY: 74460

African (AFR) AF: 0.0000722 AC: 3 AN: 41572

American (AMR) AF: 0.000980 AC: 15 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000530 AC: 36 AN: 67982

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.000328 Hom.: 0

Bravo AF: 0.000453

ExAC AF: 0.000237 AC: 26

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	0.13
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	23
DANN	Benign	0.43
DEOGEN2	Benign	0.0046	T
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.41	N
LIST_S2	Benign	0.38	T
M_CAP	Uncertain	0.095	D
MetaRNN	Benign	0.025	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.10	N
PhyloP100		2.9
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	0.45	N
REVEL	Benign	0.079
Sift	Benign	0.19	T
Sift4G	Uncertain	0.054	T
Polyphen		0.080	B
Vest4		0.14
MVP		0.49
MPC		0.74
ClinPred		0.036	T
GERP RS		3.2
Varity_R		0.14
gMVP		0.47
Mutation Taster		=86/14	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: rs771786704; hg19: chr19-19368807;