6-114057766-A-T

Variant names:

• chr6-114057766-A-T
• NM_153612.4:c.532T>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_153612.4(HS3ST5):​c.532T>A​(p.Leu178Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: HS3ST5 NM_153612.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.35
• Publications: 0 publications found

Genes affected

HS3ST5 (HGNC:19419): (heparan sulfate-glucosamine 3-sulfotransferase 5) HS3ST5 belongs to a group of heparan sulfate 3-O-sulfotransferases (EC 2.8.2.23) that transfer sulfate from 3-prime-phosphoadenosine 5-prime phosphosulfate (PAPS) to heparan sulfate and heparin (Mochizuki et al., 2003 [PubMed 12740361]).[supplied by OMIM, Mar 2008]

HDAC2-AS2 (HGNC:43590): (HDAC2 and HS3ST5 antisense RNA 2)

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.774

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_153612.4. 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
	HS3ST5	NM_153612.4	MANE Select	c.532T>A	p.Leu178Met	missense	Exon 5 of 5	NP_705840.2
	HS3ST5	NM_001387039.1		c.532T>A	p.Leu178Met	missense	Exon 4 of 4	NP_001373968.1	Q8IZT8
	HS3ST5	NM_001387040.1		c.532T>A	p.Leu178Met	missense	Exon 3 of 3	NP_001373969.1	Q8IZT8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HS3ST5	ENST00000312719.10	TSL:2 MANE Select	c.532T>A	p.Leu178Met	missense	Exon 5 of 5	ENSP00000427888.1	Q8IZT8
	HDAC2-AS2	ENST00000519104.5	TSL:1	n.1311-31171A>T		intron	N/A
	HS3ST5	ENST00000900060.1		c.532T>A	p.Leu178Met	missense	Exon 6 of 6	ENSP00000570119.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

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	Uncertain	0.46
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.53	D
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.77	D
MetaSVM	Uncertain	0.20	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		2.3
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-2.0	N
REVEL	Pathogenic	0.71
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.63
MutPred		0.73		Loss of catalytic residue at L178 (P = 0.0196)
MVP		0.68
MPC		0.82
ClinPred		0.98	D
GERP RS		1.2
Varity_R		0.67
gMVP		0.61
Mutation Taster		=33/67	disease causing

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

hg19: chr6-114378930;