rs368742889

Variant names:

• chr2-128268265-C-A
• rs368742889
• NM_004807.3:c.1133G>T

Your query was ambiguous. Multiple possible variants found:

• chr2-128268265-C-A
• chr2-128268265-C-G
• chr2-128268265-C-T

Variant summary

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

The NM_004807.3(HS6ST1):​c.1133G>T​(p.Arg378Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,666 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R378C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: HS6ST1 NM_004807.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.86
• Publications: 0 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=0.2723812).

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.1133G>T	p.Arg378Leu	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.1133G>T	p.Arg378Leu	missense	Exon 2 of 2	ENSP00000259241.6	O60243-1
	HS6ST1	ENST00000469019.1	TSL:4	n.361-21740G>T		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459666 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726118

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33444

American (AMR) AF: 0.00 AC: 0 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26108

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86190

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52438

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5226

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111610

Other (OTH) AF: 0.00 AC: 0 AN: 60264

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	0.011	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.47	T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.076
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.23	D
MetaRNN	Benign	0.27	T
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		1.9
PrimateAI	Uncertain	0.79	T
PROVEAN	Uncertain	-4.2	D
REVEL	Uncertain	0.39
Sift	Benign	0.10	T
Sift4G	Uncertain	0.0080	D
Polyphen		0.0010	B
Vest4		0.22
MutPred		0.61		Loss of MoRF binding (P = 0.0106)
MVP		0.71
ClinPred		0.94	D
GERP RS		4.3
Varity_R		0.14
gMVP		0.52
Mutation Taster		=66/34	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: rs368742889; hg19: chr2-129025839;