chr2-128268197-C-T

Variant names:

• chr2-128268197-C-T
• rs1263025168
• NM_004807.3:c.1201G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004807.3(HS6ST1):​c.1201G>A​(p.Glu401Lys) 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 benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000069 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HS6ST1 NM_004807.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.52
• Publications: 2 publications found

Genes affected

HS6ST1 (HGNC:5201): (heparan sulfate 6-O-sulfotransferase 1) The protein encoded by this gene is a member of the heparan sulfate biosynthetic enzyme family. Heparan sulfate biosynthetic enzymes are key components in generating a myriad of distinct heparan sulfate fine structures that carry out multiple biological activities. This enzyme is a type II integral membrane protein and is responsible for 6-O-sulfation of heparan sulfate. This enzyme does not share significant sequence similarity with other known sulfotransferases. A pseudogene located on chromosome 1 has been found for this gene. [provided by RefSeq, Jul 2008]

HS6ST1 Gene-Disease associations (from GenCC):

• hypogonadotropic hypogonadism

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Kallmann syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hypogonadotropic hypogonadism 15 with or without anosmia

  Inheritance: Unknown, AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Laboratory for Molecular Medicine

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.4054811).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004807.3. 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
	HS6ST1	NM_004807.3	MANE Select	c.1201G>A	p.Glu401Lys	missense	Exon 2 of 2	NP_004798.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HS6ST1	ENST00000259241.7	TSL:1 MANE Select	c.1201G>A	p.Glu401Lys	missense	Exon 2 of 2	ENSP00000259241.6	O60243-1
	HS6ST1	ENST00000469019.1	TSL:4	n.361-21672G>A		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000825 AC: 2 AN: 242526 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000101

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000917

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000686 AC: 10 AN: 1457862 Hom.: 0 Cov.: 32 AF XY: 0.00000690 AC XY: 5 AN XY: 725110

African (AFR) AF: 0.0000299 AC: 1 AN: 33408

American (AMR) AF: 0.00 AC: 0 AN: 44628

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26084

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39656

South Asian (SAS) AF: 0.00 AC: 0 AN: 86048

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52260

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4458

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1111162

Other (OTH) AF: 0.0000166 AC: 1 AN: 60158

GnomAD4 genome Cov.: 33

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	Pathogenic	0.73
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.26	T
Eigen	Uncertain	0.20
Eigen_PC	Benign	0.22
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.52	D
MetaRNN	Benign	0.41	T
MetaSVM	Uncertain	-0.020	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		3.5
PrimateAI	Pathogenic	0.80	D
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.56
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.012	D
Polyphen		0.91	P
Vest4		0.31
MutPred		0.34		Gain of MoRF binding (P = 0.0031)
MVP		0.81
ClinPred		0.72	D
GERP RS		4.2
Varity_R		0.58
gMVP		0.54
Mutation Taster		=70/30	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: rs1263025168; hg19: chr2-129025771;